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Cited by 21Protein Kinase Regulation and GTPase SignalingCellular transport and secretionProtein Structure and Dynamics

RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors

Open access
Thompson, Andrew P., Bitsina, Christina, Gray, Janine L., von Delft, Frank, Brennan, Paul E.·2021·Journal of Biological Chemistry
DOI 10.1016/j.jbc.2021.100521PMC PMC8063744
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Abstract

The human dedicator of cytokinesis (DOCK) family consists of 11 structurally conserved proteins that serve as atypical RHO guanine nucleotide exchange factors (RHO GEFs). These regulatory proteins act as mediators in numerous cellular cascades that promote cytoskeletal remodeling, playing roles in various crucial processes such as differentiation, migration, polarization, and axon growth in neurons. At the molecular level, DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process that is otherwise too slow for rapid spatiotemporal control of cellular signaling. Here, we provide an overview of the biological and structural characteristics for the various DOCK proteins and describe how they differ from other RHO GEFs and between DOCK subfamilies. The expression of the family varies depending on cell or tissue type, and they are consequently implicated in a broad range of disease phenotypes, particularly in the brain. A growing body of available structural information reveals the mechanism by which the catalytic DHR2 domain elicits nucleotide dissociation and also indicates strategies for the discovery and design of high-affinity small-molecule inhibitors. Such compounds could serve as chemical probes to interrogate the cellular function and provide starting points for drug discovery of this important class of enzymes.

AI snapshot

Written from the paper’s full text.

TL;DR

The review summarizes the 11-member DOCK family of atypical RHO guanine nucleotide exchange factors (GEFs), their DHR1/DHR2 architecture, substrate specificity, disease associations, and the structural mechanism by which DHR2 promotes GDP release. It highlights DOCK–GTPase complexes as potential targets for selective small-molecule inhibitors.

Key findings

  • The DOCK family comprises 11 proteins in four subfamilies: DOCK-A (DOCK1, 2, 5), DOCK-B (DOCK3, 4), DOCK-C (DOCK6, 7, 8), and DOCK-D (DOCK9, 10, 11); they use DHR1/DHR2 domains rather than the DH/PH architecture of the larger DH GEF class.
  • The DHR2 catalytic mechanism, first detailed for DOCK9–CDC42, involves three features that reduce GDP affinity: switch 1 displacement abolishes the Phe28–guanine interaction, P-loop Cys18 rotates away from the β-phosphate, and the α10 insert places a conserved valine (DOCK9 Val1951; DOCK2 Val1539) to occlude Mg²⁺; replacing Val1951 with alanine severely reduces DOCK GEF activity.
  • Substrate specificity generally follows subfamily: DOCK-A/B activate RAC GTPases, DOCK-D activate CDC42, and DOCK-C activate both CDC42 and RAC1 except DOCK8, which appears CDC42-specific; DOCK10 can bind CDC42 and RAC3, and DOCK7 has dual specificity with a slight preference for CDC42.
  • Disease links include DOCK2 in immunodeficiency and Alzheimer’s disease, DOCK3 in developmental/motor disorders and AD, DOCK4 in autism/dyslexia/schizophrenia and cancer metastasis, DOCK6 in Adams–Oliver syndrome, DOCK7 in epileptic encephalopathy, DOCK8 in immunodeficiency and multiple sclerosis, and DOCK10 in leukemia, multiple sclerosis, and aging.

Methods

  • Narrative review; no new experimental data are reported. It synthesizes published biological, expression, disease, and structural literature on DOCK proteins.
  • Structural evidence includes X-ray, cryo-EM, and NMR structures listed in Table 1, such as full-length DOCK2–ELMO1–RAC1 cryo-EM structures (PDB 6TGB/6TGC), DOCK9–DHR2–CDC42 structures (2WM9/2WMN/2WMO), DOCK7–DHR2–CDC42 structures (6AJ4/6AJL), and DOCK10–DHR2 complexes (6TM1/6TKY/6TKZ).
  • Expression and localization data are drawn from the Human Protein Atlas; structural prediction used HHpred, and the main analysis is comparative discussion of DHR2 lobes A–C, GEF mechanism, and therapeutic targeting strategies.

Limitations

  • Stated: gaps remain in DOCK knowledge; most RHO GTPase research has been limited to RAC1, CDC42, and RHOA; there are few small-molecule inhibitors for DOCKs; and the remaining RHO GTPase subfamilies and their cognate DOCK GEFs need similar investigation.
  • Stated: DOCK7 and DOCK8 structures lack lobe A, some structures are “to be published” (e.g., DOCK10 complexes, DOCK9 PH), and the atomic binding mode of a reported DOCK5 inhibitor is not publicly known.
  • Evident: as a narrative review, it does not conduct a systematic search, meta-analysis, or primary validation; several structural and disease conclusions rely on cited studies or homology-based prediction.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.jbc.2021.100521

Cites

138 of 138 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

78 of 146 cited sources checked · 45 supported · 2 flagged · accuracy not yet measured

  • Premisecitation

    DOCK5 preferentially activates RAC1 over other RHO or RAC GTPases.

    “DOCK5, one of the least studied family members, preferentially activates RAC1 over other RHO or RAC GTPases (91).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [91] Ferrandez, 2017, Allosteric inhibition of the guanine nucleotide exchange factor DOCK5 by a small molecule, Sci. Rep. source

      The Results section (‘Specificity and regulation of the DHR2 domain of human DOCK5’) reports that DOCK5DHR2 activates Rac1 and Rac2 with nearly identical efficiencies: 3 × 10⁴ and 3.2 × 10⁴ M⁻¹s⁻¹, respectively. It is inactive toward the tested RhoA, Cdc42, and RhoG, but the results do not show a preference for Rac1 over other Rac GTPases. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Genome-wide association studies have identified DOCK5 as a high-risk genetic factor associated with familial Parkinson's disease pathology.

    “In neurology, genome-wide association studies (GWAS) have identified this gene as a high-risk genetic factor associated with familial Parkinson's disease (PD) pathology (95).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [95] Pankratz, 2011, Copy number variation in familial Parkinson disease, PLoS One source

      The Results report an initially significant DOCK5 association, but the Discussion says the novel locus could not be validated by independent molecular tests. It concludes that the apparent DOCK5 association was likely spurious, caused by different DNA sources for cases and controls—not evidence that DOCK5 is an established high-risk factor for familial PD. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisenone given

    DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process otherwise too slow for rapid spatiotemporal control of cellular signaling.

    “At the molecular level, DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process that is otherwise too slow for rapid spatiotemporal control of cellular signaling.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [33] Pakes, 2013, Zizimin and Dock guanine nucleotide exchange factors in cell function and disease, Small GTPases source

      The Introduction (page not available in our copy) says the DHR2 domain is responsible for guanine nucleotide exchange factor activity, supporting the claim that it facilitates nucleotide exchange in small GTPases. It does not address the rate of nucleotide dissociation without a GEF or say that it is too slow for rapid spatiotemporal control of signaling. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [34] Brugnera, 2002, Unconventional Rac-GEF activity is mediated through the Dock180–ELMO complex, Nat. Cell Biol. source
    • cites [35] Yang, 2009, Activation of rho GTPases by DOCK exchange factors is mediated by a nucleotide sensor, Science source
  • Premisecitation

    DOCK2 has been implicated in the pathogenesis of Alzheimer's disease by enhancing amyloid beta plaque formation.

    “It has been implicated in the pathogenesis of AD by enhancing amyloid beta (Aβ) plaque formation (66, 67).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [66] Cimino, 2009, DOCK2 is a microglial specific regulator of central nervous system innate immunity found in normal and Alzheimer’s disease brain, Am. J. Pathol. source

      The ‘DOCK2 in Normal and AD Human Brain’ section reports that DOCK2-positive microglia are associated with amyloid-beta plaques, supporting a link to Alzheimer’s pathology. It does not show that DOCK2 enhances plaque formation; the Discussion instead describes plaques as recruiting microglia and says DOCK2 is unlikely to mediate the phagocytic suppression discussed there. Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [67] Cimino, 2013, Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of Alzheimer’s disease, Exp. Mol. Pathol. source
  • Premisecitation

    The DHR2 domain is responsible for GEF activity in a mechanism distinct from that of DH-containing GEFs.

    “The DHR2 domain is responsible for GEF activity in a mechanism that is distinct from that of DH-containing GEFs (33, 34, 35).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [33] Pakes, 2013, Zizimin and Dock guanine nucleotide exchange factors in cell function and disease, Small GTPases source

      The Introduction states that the DHR2 domain is responsible for GEF activity. It does not describe the mechanism or compare it with that of DH-containing GEFs, so the claimed mechanistic distinction is not supported by this paper's text. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [34] Brugnera, 2002, Unconventional Rac-GEF activity is mediated through the Dock180–ELMO complex, Nat. Cell Biol. source
    • cites [35] Yang, 2009, Activation of rho GTPases by DOCK exchange factors is mediated by a nucleotide sensor, Science source
  • May combine two claims. 35
  • Classified as probably not a substantial claim. 41

  • May combine two claims.

    Premisecitation

    DOCK families A and B contain N-terminal SH3 domains and a C-terminal proline-rich region that bind each other to maintain autoinhibition, which is alleviated upon binding adaptor proteins such as ELMO1.

    “Generally DOCK families A and B contain N-terminal SRC Homology 3 (SH3) domains and a C-terminal proline-rich region that bind each other to maintain the protein in an autoinhibited state, an interaction that is alleviated upon binding adaptor proteins such as engulfment and cell motility protein 1 (ELMO1) (36, 37).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [36] Shi, 2013, Dock protein family in brain development and neurological disease, Commun. Integr. Biol. source

      The Introduction says Dock-A and Dock-B members have an N-terminal SH3 domain and a proline-rich C-terminus. The Regulation of Dock Activity section says ELMO binds the SH3 domain and releases Dock autoinhibition, but it does not say the SH3 domain and proline-rich region bind each other to maintain that state. No page numbers are available in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [37] Hanawa-Suetsugu, 2012, Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms, Proc. Natl. Acad. Sci. U. S. A. source

      The Abstract and Results identify an N-terminal SH3 domain in DOCK2 and show that ELMO1 binding relieves DOCK2 autoinhibition. But the Results identify the proline-rich tail as part of ELMO1, not DOCK2; the DOCK2 regions that associate during autoinhibition are its N-terminal ELMO-interacting region and C-terminal DHR-2-containing region. The paper therefore does not support the claimed intramolecular SH3–proline-rich interaction in DOCK proteins. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    DOCK2 activates RAC GTPases and is predominantly expressed in hematopoietic cells.

    “DOCK2, responsible for activating RAC GTPases, is predominantly expressed in hematopoietic cells (59, 60, 61, 62).”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [59] Ushijima, 2018, The Rac activator DOCK2 mediates plasma cell differentiation and IgG antibody production, Front. Immunol. source
    • cites [60] Wu, 2019, DOCK2 expression affects leukemogenesis and disease progression in a murine model of FLT3/ITD acute myeloid leukemia, Blood source
    • cites [61] Chen, 2018, Dock2 in the development of inflammation and cancer, Eur. J. Immunol. source
    • cites [62] Kikuchi, 2008, Dock2 participates in bone marrow lympho-hematopoiesis, Biochem. Biophys. Res. Commun. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Deregulation of RHO GTPase signaling has a significant impact toward the development of autism spectrum disorders.

    “Similarly, emerging evidence supports that deregulation of RHO GTPase signaling has a significant impact toward the development of autism spectrum disorders (ASDs) (23).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] Guo, 2020, Rho GTPase regulators and effectors in autism spectrum disorders: Animal models and insights for therapeutics, Cells source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Multiple immunodeficiencies have been linked to DOCK2 mutations.

    “Multiple immunodeficiencies have also been linked to DOCK2 mutations (64).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [64] Dobbs, 2015, Inherited DOCK2 deficiency in patients with early-onset invasive infections, N. Engl. J. Med. source

      The Discussion identifies DOCK2 mutations as the cause of a distinctive type of combined immunodeficiency with defects in several aspects of immunity. It does not establish that DOCK2 mutations are linked to multiple distinct immunodeficiency disorders. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The DOCK-C subfamily has dual binding capability, activating both CDC42 and RAC1, except DOCK8, which appears to be a specific CDC42 GEF.

    “The DOCK-C subfamily has dual binding capability, activating both CDC42 and RAC1, except for DOCK8, which appears to be a specific CDC42 GEF (38).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Chang, 2020, Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state, Nat. Commun. source

  • May combine two claims.

    Premisecitation

    DOCK-A and DOCK-B proteins activate RAC GTPases specifically, whereas the DOCK-D subfamily activates CDC42.

    “Generally, DOCK-A and DOCK-B proteins activate the RAC GTPases specifically (35, 41), whereas the DOCK-D subfamily is responsible for activating CDC42.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [35] Yang, 2009, Activation of rho GTPases by DOCK exchange factors is mediated by a nucleotide sensor, Science source
    • cites [41] Kulkarni, 2011, Multiple factors confer specific Cdc42 and Rac protein activation by dedicator of cytokinesis (DOCK) nucleotide exchange factors, J. Biol. Chem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DH GEFs constitute the larger of the two classes, with over 70 members.

    “DH GEFs constitute the larger of the two classes, with over 70 members (30, 31).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [30] Cook, 2014, Rho guanine nucleotide exchange factors: Regulators of rho GTPase activity in development and disease, Oncogene source

      In “The discovery of RhoGEFs: diverse in numbers and structure” (page not supplied), the paper reports 70 human Dbl-family RhoGEFs and 11 human DOCK-family RhoGEFs. This supports that the DH/Dbl class is larger, but not the claim that it has over 70 members. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [31] Jaiswal, 2013, Deciphering the molecular and functional basis of Dbl family proteins, J. Biol. Chem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Overactivation of RHO subfamily GTPases such as RAC1 and CDC42 promotes hyperactivation of critical signaling cascades leading to cancer.

    “However, overactivation of the RHO subfamily such as RAS-related C3 botulinum toxin substrate 1 (RAC1) and cell division cycle 42 homolog (CDC42) are also known to promote the hyperactivation of critical signaling cascades leading to cancer (10, 13, 17).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [10] Boettner, 2002, The role of Rho GTPases in disease development, Gene source
    • cites [13] Oxford, 2003, Review article: The role of Ras superfamily proteins in bladder cancer progression, J. Urol. source
    • cites [17] Maldonado, 2020, Targeting Rac and Cdc42 GEFs in metastatic cancer, Front. Cell Dev. Biol. source

      The Introduction describes Rac and Cdc42 as drivers of cancer progression and metastasis and says they activate downstream signaling cascades. The Targeting Rac and Cdc42/GEF Interaction section says Rac1 and Cdc42 can be hyperactivated in cancer. The copy does not establish that their overactivation hyperactivates those cascades or leads to the initial development of cancer, rather than promoting progression. (LLM, conf=0.81)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Inhibition of GEF activity would arrest the given GTPase signaling pathways, constituting a promising target for small-molecule therapeutic development.

    “As evidenced by reports of small molecules targeting the RAS GEF SOS1, inhibition of GEF activity would thus arrest the given GTPase signaling pathways, constituting a promising target for small-molecule therapeutic development (11, 12).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [11] Hillig, 2019, Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction, Proc. Natl. Acad. Sci. U. S. A. source

      The Abstract and Discussion report that small-molecule SOS1 inhibition down-regulated active RAS and completely inhibited the RAS-RAF-MEK-ERK pathway in cells with wild-type KRAS. The Discussion reports only an approximately 50% reduction in phospho-ERK activity in a mutant KRAS cell line. The paper supports GEF inhibition as a promising therapeutic approach, but not the unqualified claim that it would arrest GTPase signaling pathways generally. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [12] Hofmann, 2020, BI-3406, a potent and selective SOS1::KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition, Cancer Discov. source

      The Introduction identifies SOS1 as a KRAS guanine exchange factor, and the Discussion reports that the small-molecule inhibitor BI-3406 reduces RAS-GTP levels and curtails MAPK signaling. This supports SOS1 inhibition as a promising therapeutic approach, but the paper does not show that GEF inhibition arrests GTPase signaling altogether or establish the claim for GTPase pathways generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DOCK1 has reported roles in cell migration, invasion, and phagocytosis.

    “It has reported roles in cell migration, invasion, and phagocytosis (48, 51, 52, 53, 54).”
    Quote in the paperNot a substantial claim4 of 5 sources checked
    • cites [48] Namekata, 2014, Dock GEFs and their therapeutic potential: Neuroprotection and axon regeneration, Prog. Retin. Eye Res. source
    • cites [51] Liang, 2018, Downregulation of Dock1 and Elmo1 suppresses the migration and invasion of triple-negative breast cancer epithelial cells through the RhoA/Rac1 pathway, Oncol. Lett. source

      The Results and Discussion report that reducing Dock1 suppresses migration and invasion in MDA-MB-231 cells. The Introduction mentions phagocytosis of apoptotic cells as a role of Elmo1, not Dock1, so this copy does not establish that part of the claim for Dock1. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [52] Gumienny, 2001, CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration, Cell source
    • cites [53] Grimsley, 2004, Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration, J. Biol. Chem. source

      The migration-results section reports that coexpression of Dock180 (DOCK1) and ELMO1 strongly promoted LR73 cell migration. The Discussion also describes their role in phagocytosis. Neither those passages nor a search of our copy for “invasion” supports the invasion part of the claim. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [54] Tomino, 2018, DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1P29S mutation, Biochem. Biophys. Res. Commun. source

  • May combine two claims.

    Findingcitation

    A recent cryo-electron microscopy structure of the full-length DOCK2-RAC1-ELMO1 complex is consistent with prior predictions and provides the first high-resolution view of conformational and phosphorylation events leading to activation of the complete complex.

    “A recent cryo-electron microscopy-derived structure of this signaling complex using the full-length proteins is consistent with these predictions and provides the first high-resolution view of the conformational and phosphorylation events leading to activation of the complete complex (Fig. 3) (38).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [38] Chang, 2020, Structure of the DOCK2−ELMO1 complex provides insights into regulation of the auto-inhibited state, Nat. Commun. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK7 has a role in migration of neuroblasts in developing mouse brains.

    “More recently a role for DOCK7 in the migration of neuroblasts in developing mouse brains was also identified (107).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [107] Nakamuta, 2017, Dual role for DOCK7 in tangential migration of interneuron precursors in the postnatal forebrain, J. Cell Biol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK7 activity leads to migration in Schwann cells.

    “Interestingly, DOCK7 activity leads to migration in Schwann cells, and knocking down expression leads to increased myelination and differentiation (109).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [109] Yamauchi, 2011, The atypical guanine-nucleotide exchange factor, Dock7, negatively regulates Schwann cell differentiation and myelination, J. Neurosci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Four independent studies have identified mutations in the DOCK6 gene responsible for or associated with the development of Adams-Oliver Syndrome.

    “Four independent studies have identified mutations in the DOCK6 gene responsible for or associated with the development of the rare Adams–Oliver Syndrome (98, 99, 100, 101).”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [98] Sukalo, 2015, DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies, Hum. Mutat. source
    • cites [99] Wang, 2019, Novel compound heterozygous mutations of the DOCK6 gene in a familial case of Adams-Oliver syndrome 2, Gene source
    • cites [100] Alzahem, 2020, A novel variant in DOCK6 gene associated with Adams-Oliver syndrome type 2, Ophthalmic Genet. source
    • cites [101] Dudoignon, 2020, Expanding the phenotype in Adams-Oliver syndrome correlating with the genotype, Am. J. Med. Genet. A source

  • May combine two claims.

    Premisecitation

    DOCK3 is a GEF for RAC1 and acts as a regulator of actin reorganization in neuronal tissue.

    “DOCK3, a GEF for RAC1, acts as regulator of actin reorganization in neuronal tissue (69, 70, 71, 72).”
    Quote in the paperNot a substantial claim4 of 4 sources checked
    • cites [69] Laurin, 2014, Insights into the biological functions of Dock family guanine nucleotide exchange factors, Genes Dev. source
    • cites [70] Wiltrout, 2019, Variants in DOCK3 cause developmental delay and hypotonia, Eur. J. Hum. Genet. source
    • cites [71] Namekata, 2004, MOCA induces membrane spreading by activating Rac1, J. Biol. Chem. source

      The “MOCA Binds to and Activates Rac1” passage reports that MOCA (Dock3) promotes guanine nucleotide exchange for Rac1. The Discussion links MOCA to actin reorganization during neural extension, but says it *may* be involved; the claim presents that proposed neuronal role as established. Page numbers are not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [72] Namekata, 2010, Dock3 induces axonal outgrowth by stimulating membrane recruitment of the WAVE complex, Proc. Natl. Acad. Sci. U. S. A. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK7 is upregulated in astrocytoma human glioblastoma compared with nonneoplastic brain.

    “DOCK7-controlled migration can also be pathological; it was identified to be required for human hepatocyte growth factor (HGF)-induced glioblastoma tumor cell invasion, with upregulated DOCK7 found in astrocytoma human glioblastoma compared with nonneoplastic brain (108).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [108] Murray, 2014, Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation, Br. J. Cancer source

  • May combine two claims.

    Premisecitation

    DOCK4 activates RAC and RAP1 GTPases.

    “DOCK4 activates RAC and RAP1 GTPases (82).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [82] Yajnik, 2003, DOCK4, a GTPase activator, is disrupted during tumorigenesis, Cell source

      The Results ('Activation of Rap GTPase by DOCK4') report strong Rap activation by wild-type DOCK4, but explicitly state that it had no effect on Rac. Rac activation was observed with the tumor-associated Pro1718Leu mutant, not wild-type DOCK4. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK7 is highly expressed in the brain.

    “It is highly expressed in the brain, where it has roles in axon formation, polarity, and myelination (42, 48, 104, 105).”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [42] Kukimoto-Niino, 2019, Structural basis for the dual substrate specificity of DOCK7 guanine nucleotide exchange factor, Structure source
    • cites [48] Namekata, 2014, Dock GEFs and their therapeutic potential: Neuroprotection and axon regeneration, Prog. Retin. Eye Res. source
    • cites [104] Watabe-Uchida, 2006, The Rac activator DOCK7 regulates neuronal polarity through local phosphorylation of Stathmin/Op18, Neuron source
    • cites [105] Pinheiro, 2006, Nervous Rac: DOCK7 regulation of axon formation, Neuron source

  • May combine two claims.

    Premisecitation

    Knocking down DOCK7 expression leads to increased myelination and differentiation.

    “Interestingly, DOCK7 activity leads to migration in Schwann cells, and knocking down expression leads to increased myelination and differentiation (109).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [109] Yamauchi, 2011, The atypical guanine-nucleotide exchange factor, Dock7, negatively regulates Schwann cell differentiation and myelination, J. Neurosci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK8 is a CDC42-specific GEF.

    “DOCK8 is a CDC42-specific GEF (113).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [113] Harada, 2012, DOCK8 is a Cdc42 activator critical for interstitial dendritic cell migration during immune responses, Blood source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DOCK7 has roles in axon formation, polarity, and myelination.

    “It is highly expressed in the brain, where it has roles in axon formation, polarity, and myelination (42, 48, 104, 105).”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [42] Kukimoto-Niino, 2019, Structural basis for the dual substrate specificity of DOCK7 guanine nucleotide exchange factor, Structure source
    • cites [48] Namekata, 2014, Dock GEFs and their therapeutic potential: Neuroprotection and axon regeneration, Prog. Retin. Eye Res. source
    • cites [104] Watabe-Uchida, 2006, The Rac activator DOCK7 regulates neuronal polarity through local phosphorylation of Stathmin/Op18, Neuron source

      The Discussion (page not provided) says DOCK7 is highly expressed in the developing brain and is required for axon formation and neuronal polarization. Our copy does not establish a role in myelination, so that part of the cited claim is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [105] Pinheiro, 2006, Nervous Rac: DOCK7 regulation of axon formation, Neuron source

  • May combine two claims.

    Premisecitation

    A region of DOCK7 including the DHR1 binds TACC3, and this interaction is required for neural genesis and nuclear migration.

    “A region of DOCK7 that includes the DHR1 was identified to bind the centrosome-associated protein TACC3, an interaction that was required for neural genesis and nuclear migration (106).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [106] Yang, 2012, DOCK7 interacts with TACC3 to regulate interkinetic nuclear migration and cortical neurogenesis, Nat. Neurosci. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK10 is highly expressed in neurites of neuroblastoma cells.

    “DOCK10 is also highly expressed in neurites of neuroblastoma cells (36).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [36] Shi, 2013, Dock protein family in brain development and neurological disease, Commun. Integr. Biol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Overexpression of DOCK9 coincides with an increase in RAC1 activity.

    “Although not reported as a substrate, overexpression of DOCK9 coincided with an increase in RAC1 activity.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [122] Ruiz-Lafuente, 2018, DOCK9 induces membrane ruffles and Rac1 activity in cancer HeLa epithelial cells, Biochem. Biophys. Rep. source

  • May combine two claims.

    Premisecitation

    Knockout EAE mouse models of all DOCK-D family members were healthy and viable; DOCK9 knockout had no reported change in phenotype.

    “Knockout EAE mouse models of all DOCK-D family members were healthy and viable; DOCK9, however, had no reported change in phenotype, implying it is not involved in MS (120).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [120] Namekata, 2020, Roles of the DOCK-D family proteins in a mouse model of neuroinflammation, J. Biol. Chem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DOCK9 is widely and highly expressed throughout the body, including the brain; antibodies against two isoforms of DOCK9 indicate differing expression profiles.

    “It is widely and highly expressed throughout the body, including the brain; however, antibodies against two isoforms of DOCK9 indicated differing expression profiles (121).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [121] Parrado, 2020, Expression of DOCK9 and DOCK11 analyzed with commercial antibodies: Focus on regulation of mutually exclusive first exon isoforms, Antibodies (Basel) source

      The Introduction reports high DOCK9 mRNA expression in several tissues, including the brain, and the Abstract describes the isoforms as widely distributed; it does not say expression is high throughout the body. Results §3.3 reports differing profiles from two antibodies, but one detects DOCK9.1 while the other detects a region common to DOCK9 isoforms—not DOCK9.2 specifically. Our copy provides no page numbers for these passages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Patients with large deletions in the DOCK8 gene have increased susceptibility to pathogenic infections and exhibit allergic diseases.

    “In line with this, patients with large deletions in the DOCK8 gene experience increased susceptibility to pathogenic infections yet also exhibit allergic diseases, leading to great interest surrounding DOCK8 in the field of immunology, which has recently been reviewed in great detail (50, 115, 116).”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [50] Kunimura, 2020, DOCK family proteins: Key players in immune surveillance mechanisms, Int. Immunol. source
    • cites [115] Biggs, 2017, DOCK8 deficiency: Insights into pathophysiology, clinical features and management, Clin. Immunol. source
    • cites [116] Kearney, 2017, DOCK8 regulates signal transduction events to control immunity, Cell. Mol. Immunol. source

      The Introduction and Table 1 report that patients with DOCK8 deficiency have recurrent infections, eczema, and food allergy. The paper describes loss-of-function mutations generally, but does not establish that these manifestations occur specifically in patients with large DOCK8 deletions. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    DOCK10 is a GEF for both CDC42 and RAC GTPases.

    “DOCK10 is a GEF for both CDC42 and RAC GTPases (42, 43, 44).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [42] Kukimoto-Niino, 2019, Structural basis for the dual substrate specificity of DOCK7 guanine nucleotide exchange factor, Structure source
    • cites [43] Miyamoto, 2007, Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth, Exp. Cell Res. source
    • cites [44] Ruiz-Lafuente, 2015, Dock10, a Cdc42 and Rac1 GEF, induces loss of elongation, filopodia, and ruffles in cervical cancer epithelial HeLa cells, Biol. Open. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A point mutation in the AMPAR subunit GluA3 causes circadian rhythm disruption and intellectual disability.

    “Such an interaction is worth investigation, as a reported point mutation in the AMPAR subunit GluA3 was shown to cause circadian rhythm disruption and intellectual disability (125).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [125] Davies, 2017, A point mutation in the ion conduction pore of AMPA receptor GRIA3 causes dramatically perturbed sleep patterns as well as intellectual disability, Hum. Mol. Genet. source

      The Introduction reports a GRIA3 mutation, which affects the GluA3 subunit, in patients with profound intellectual disability and severely disrupted sleep–wake cycles. But the Results say the authors could not determine whether the sleep disturbance arose from the circadian system, and the Discussion suggests it may instead affect sleep–wake organization. Calling it a demonstrated cause of circadian rhythm disruption overstates the finding. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In HeLa epithelial cells, DOCK9 expression reduced elongated cell morphology and led to increased filopodia and membrane ruffling.

    “The role of DOCK9 in structural remodeling of cells was investigated in HeLa epithelial cells, where its expression reduced elongated cell morphology and led to increased filopodia and membrane ruffling (122).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [122] Ruiz-Lafuente, 2018, DOCK9 induces membrane ruffles and Rac1 activity in cancer HeLa epithelial cells, Biochem. Biophys. Rep. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mutations in the DOCK8 gene are associated with autism disorders.

    “Mutations in the DOCK8 gene have also been associated with autism disorders (116).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [116] Kearney, 2017, DOCK8 regulates signal transduction events to control immunity, Cell. Mol. Immunol. source

      The Introduction links DOCK8 mutations to combined immunodeficiency, and the Conclusion discusses their effects on immune function. Neither passage addresses autism; searches for autism and related neurodevelopmental terms found no supporting passage in our copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    DOCK8 knockout in mononuclear phagocytes renders them highly susceptible to cell death when migrating through tissue, releasing inflammatory cytokines.

    “Recently, it has been shown that DOCK8 knockout in mononuclear phagocytes renders them highly susceptible to cell death when migrating through tissue, releasing inflammatory cytokines in the process (117).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [117] Schneider, 2020, Migration-induced cell shattering due to DOCK8 deficiency causes a type 2-biased helper T cell response, Nat. Immunol. source

  • May combine two claims.

    Premisecitation

    The DOCK-D subfamily has roles in the immune system and neurology.

    “The DOCK-D subfamily, although not as well studied as other DOCKs, has been shown to have roles in the immune system and neurology (36, 48, 120).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [36] Shi, 2013, Dock protein family in brain development and neurological disease, Commun. Integr. Biol. source

      The Dock-D section (page unavailable) says the subfamily is relatively less studied and reports neural roles for Dock9 and possible links between Dock9 and Dock10 and neurological conditions. It says Dock11 is expressed predominantly in lymphocytes, but does not establish an immune-system role for Dock-D members; that part of the claim is not supported by this copy. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [48] Namekata, 2014, Dock GEFs and their therapeutic potential: Neuroprotection and axon regeneration, Prog. Retin. Eye Res. source
    • cites [120] Namekata, 2020, Roles of the DOCK-D family proteins in a mouse model of neuroinflammation, J. Biol. Chem. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK11 is implicated in aging processes.

    “Similar to DOCK10, several studies have implicated DOCK11 in aging processes.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [129] Sakabe, 2012, Age-related guanine nucleotide exchange factor, mouse Zizimin2, induces filopodia in bone marrow-derived dendritic cells, Immun. Ageing source
    • cites [130] Sakamoto, 2017, Involvement of Zizimin2/3 in the age-related defect of peritoneal B-1a cells as a source of anti-bacterial IgM, Int. Immunol. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK11 is linked to Fcγ and TLR4 receptor engagement.

    “It was also linked to Fcγ and TLR4 receptor engagement.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [129] Sakabe, 2012, Age-related guanine nucleotide exchange factor, mouse Zizimin2, induces filopodia in bone marrow-derived dendritic cells, Immun. Ageing source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK11 expression decreases in mouse lymphoid tissue.

    “Expression was observed to decrease in mouse lymphoid tissue, where it was reportedly involved in structural remodeling such as filopodial formation (129).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [129] Sakabe, 2012, Age-related guanine nucleotide exchange factor, mouse Zizimin2, induces filopodia in bone marrow-derived dendritic cells, Immun. Ageing source

      The Results section (“Zizimin2 is down-regulated in aged mice”; page unavailable) reports lower DOCK11/Zizimin2 expression in aged mouse spleen than in young mouse spleen. The claim omits that age comparison and broadens the finding from spleen to mouse lymphoid tissue generally. The Discussion links Zizimin2 to filopodial formation in bone marrow-derived dendritic cells, rather than demonstrating that process throughout lymphoid tissue. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK11 is involved in structural remodeling such as filopodial formation.

    “Expression was observed to decrease in mouse lymphoid tissue, where it was reportedly involved in structural remodeling such as filopodial formation (129).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [129] Sakabe, 2012, Age-related guanine nucleotide exchange factor, mouse Zizimin2, induces filopodia in bone marrow-derived dendritic cells, Immun. Ageing source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    DOCK family expression varies depending on cell or tissue type.

    “The expression of the family varies depending on cell or tissue type, and they are consequently implicated in a broad range of disease phenotypes, particularly in the brain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The DOCK GEFs do not induce changes in the switch 2 region of their GTPase substrates and conformational changes are confined to switch 1.

    “In contrast to the DH GEFs such as Kalirin, the DOCK GEFs do not induce changes in the switch 2 region of their GTPase substrates and conformational changes are confined to switch 1 (Figs. 5 and 7, A–D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Within related DOCK subfamilies, DOCKs 7, 8, 9, and 10 (DOCK-C, D members) elicit similar switch 1 conformations in their partner GTPases whether it is CDC42 or RAC1, whereas DOCK2 (DOCK-A subfamily) elicits a different conformation in the switch 1 loop of RAC1.

    “This phenomenon appears to be consistent within related DOCK subfamilies, with DOCKs 7, 8, 9, and 10 (DOCK-C, D members) eliciting similar switch 1 conformations in their partner GTPases whether it is CDC42 or RAC1, whereas DOCK2 (DOCK-A subfamily) elicits a different conformation in the switch 1 loop of RAC1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The switch 2 loop conformation in DOCK2-RAC1 is identical to that of CDC42 alone and is distinct from that observed in the RAC1-Kalirin structure.

    “The switch 2 loop conformation is identical to that of CDC42 alone and is thus distinct from that observed in the RAC1-Kalirin structure.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    The human DOCK family consists of 11 structurally conserved proteins that serve as atypical RHO guanine nucleotide exchange factors (RHO GEFs).

    “The human dedicator of cytokinesis (DOCK) family consists of 11 structurally conserved proteins that serve as atypical RHO guanine nucleotide exchange factors (RHO GEFs).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    DOCK1 is a GEF specific to the RAC subfamily of RHO GTPases.

    “DOCK1 is a GEF specific to the RAC subfamily of RHO GTPases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    GTPase affinity for guanine nucleotides is extremely high (Kd 10−7-10−11), ensuring committed states that do not spontaneously interchange and do not respond to changes in cellular nucleotide concentrations.

    “The affinity of the interaction between GTPases and either guanine nucleotides is extremely high (Kd 10−7–10−11) ensuring that these are committed states that do not spontaneously interchange; they do not respond to changes in cellular nucleotide concentrations (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Bourne, 1991, The GTPase superfamily: Conserved structure and molecular mechanism, Nature source

  • May combine two claims.

    Premisecitation

    In mouse primary hippocampal neurons, RAC1 inhibition with compound NSC23766 leads to attenuated γ-secretase activity, reduction in cellular APP, and subsequent β-amyloid plaque formation.

    “This can be inferred from mouse primary hippocampal neuronal experiments, where RAC1 inhibition with compound NSC23766 leads to attenuated γ-secretase activity, resulting in a reduction in cellular amyloid precursor protein (APP) and subsequent β-amyloid plaque formation, a hallmark of Alzheimer’s disease (AD) (29).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Boo, 2008, Rac1 changes the substrate specificity of γ-secretase between amyloid precursor protein and Notch1, Biochem. Biophys. Res. Commun. source

  • Classified as probably not a substantial claim.

    Premisecitation

    GEF-catalyzed nucleotide exchange results in an active GTPase that can transduce signals to control cellular functions.

    “In particular, GEF-catalyzed nucleotide exchange results in an active GTPase that can transduce signals to control cellular functions (10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Boettner, 2002, The role of Rho GTPases in disease development, Gene source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    RHO GTPases modulate neuronal functions, as evidenced by the implication of their dysregulation in neurological disorders.

    “RHO GTPases also modulate neuronal functions, as evidenced by the implication of their dysregulation in neurological disorders.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    RHO GTPases can be activated by two distinct classes of GEFs: DH domain containing enzymes and DOCK proteins.

    “RHO GTPases can be activated by two distinct classes of GEFs: the Dbl homology (DH) domain containing enzymes and the dedicators of cytokinesis (DOCK).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    DOCK proteins are implicated in a broad range of disease phenotypes, particularly in the brain.

    “The expression of the family varies depending on cell or tissue type, and they are consequently implicated in a broad range of disease phenotypes, particularly in the brain.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    DOCK-C and DOCK-D members do not contain the SH3 domain and therefore do not bind the ELMO1 adapter.

    “Unlike the DOCK-A and B proteins, DOCK-C and D members do not contain the SH3 domain and therefore do not bind the ELMO1 adapter.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The DOCK family is classified into four subfamilies: DOCK-A (DOCK1, 2, 5), DOCK-B (DOCK3, 4), DOCK-C (DOCK6, 7, 8), and DOCK-D (DOCK9, 10, 11).

    “Based on sequence homology, phylogeny, and substrate specificity, the DOCK family is classified into four subfamilies: DOCK-A (DOCK1, 2, 5), DOCK-B (DOCK3, 4), DOCK-C (DOCK6, 7, 8), and DOCK-D (DOCK9, 10, 11) (Fig. 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    There are only 11 DOCK proteins, characterized by DHR1 and DHR2 domains instead of the canonical DH/PH domain structure.

    “In contrast, there are only 11 DOCK proteins, and they are characterized by two structurally conserved domains: DOCK homology regions 1 and 2 (DHR1, DHR2) instead of the canonical DH/PH domain structure of the larger RHO GEF family.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In mammals, the RHO family consists of 20 members distributed into eight subfamilies based on sequence homology.

    “In mammals, the RHO family consists of 20 members in total, further distributed into eight subfamilies based on sequence homology: CDC42, RAC, RHO, RHOBTB, RHOD/F, RHOH, RHOU/V, and RND (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] DeGeer, 2013, Rho GTPases in neurodegeneration diseases, Exp. Cell Res. source

  • May combine two claims.

    Premisecitation

    DOCK6 interacts with both CDC42 and RAC1, but not RHOA, to regulate actin remodeling, manifesting as neuron growth and regeneration in the brain.

    “DOCK6 is reported to interact with both CDC42 and RAC1 (but not RHOA) in order to regulate actin remodeling, manifesting as neuron growth and regeneration in the brain (40, 43).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Miyamoto, 2013, Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons, Sci. Signal. source
    • cites [43] Miyamoto, 2007, Dock6, a Dock-C subfamily guanine nucleotide exchanger, has the dual specificity for Rac1 and Cdc42 and regulates neurite outgrowth, Exp. Cell Res. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DOCK8 is predominantly expressed in blood, bone marrow, and lymphoid tissues by RNA, while protein expression is high in lung and lower in other tissues.

    “It is predominantly observed in the blood, bone marrow, and lymphoid tissues by RNA, while protein expression also indicates high levels in the lung and lower levels in other tissues (Human Protein Atlas).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Human Protein Atlas

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    DOCK8 is required for B-cell, T-cell, and natural killer cell function.

    “DOCK8 regulates a broad range of signaling cascades to control survival, motility, and synapse formation in lymphocytes; it is required for B-cell, T-cell, and natural killer cell function (114).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [114] Kearney, 2017, DOCK8 drives Src-dependent NK cell effector function, J. Immunol. source

  • May combine two claims.

    Premisecitation

    DOCK7 is a GEF for both RAC and CDC42 GTPases, with a slight catalytic preference for CDC42.

    “DOCK7 exhibits dual specificity for RAC and CDC42 GTPases, with a slight catalytic preference for CDC42 (42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Kukimoto-Niino, 2019, Structural basis for the dual substrate specificity of DOCK7 guanine nucleotide exchange factor, Structure source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DOCK7 is widely expressed throughout the body, with high levels in endocrine, eye, and reproductive tissues.

    “It is also expressed widely throughout the body, with high levels noted in endocrine, eye, and reproductive tissues according to RNA expression data (Human Protein Atlas).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Human Protein Atlas

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK9 is a CDC42 GEF.

    “DOCK9 is a CDC42 GEF (35).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Yang, 2009, Activation of rho GTPases by DOCK exchange factors is mediated by a nucleotide sensor, Science source

  • May combine two claims.

    Interpretationcitation

    DOCK10 may have a role in neurology and immunity.

    “Unlike DOCK9, it has tissue-selective expression noted in the brain, female reproductive tissues, skin, and lymphoid tissues (Human Protein Atlas), implying it may have a role in neurology and immunity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Human Protein Atlas

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    DOCK9's ubiquitous expression increases the likelihood of off-target effects when inhibiting this protein.

    “However, its ubiquitous expression increases the likelihood of off-target effects when inhibiting this protein.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK10 expression is induced by interleukin-4 (IL4).

    “DOCK10 expression is reportedly induced by interleukin-4 (IL4), which activates signaling pathways involved in cell growth and differentiation (126).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Yelo, 2008, Dock10, a novel CZH protein selectively induced by interleukin-4 in human B lymphocytes, Mol. Immunol. source

  • May combine two claims.

    Interpretationnone given

    DOCK9 is representative of all known DOCK-C and D GEFs, which elicit the same conformational change.

    “Here, DOCK9 is representative of all known DOCK-C and D GEFs, which elicit the same conformational change.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Kalirin is representative of all DH GEFs, which elicit similar switch loop conformational changes throughout the family.

    “Kalirin is representative of all DH GEFs, which elicit similar switch loop conformational changes throughout the family.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    DOCK11 is distributed among various tissues throughout the body.

    “It is also distributed among various tissues throughout the body (Human Protein Atlas).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Human Protein Atlas

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Structural remodeling processes that result in motility, membrane organization, axon organization, myelination, and differentiation are consequences of acting on RHO GTPases.

    “Structural remodeling processes that result in motility, membrane organization, axon organization, myelination, and differentiation are all consequences of acting on the RHO GTPases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    DOCK proteins share common features in their biological functions.

    “As a family, the DOCK proteins share common features in their biological functions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    DOCKs are distinct structurally and mechanistically from the larger DBL homology (DH) family of RHO GEFs.

    “Distinct structurally and mechanistically from the larger DBL homology (DH) family of RHO GEFs, DOCKs present an opportunity for selective modulation of GTPase pathways with small molecules.”
    Quote in the paperSubstantial claim
68 of 68

  • The paper relies on this without support.

    DOCK GEFs are responsible for controlling many essential biological processes, particularly structural remodeling of cells leading to migration, differentiation, and proliferation in many cell types.

    “Acting on the universal and pleiotropic GTPases, the DOCK GEFs are responsible for controlling many essential biological processes, particularly structural remodeling of cells leading to migration, differentiation, and proliferation in many cell types.”

  • The paper relies on this without support.

    The DOCK family of proteins is implicated in various diseases, ranging from cancer to neurodegeneration.

    “This family of proteins is consequently implicated in various diseases, ranging from cancer to neurodegeneration.”

  • The paper relies on this without support.

    The vast majority of investigation into RHO GTPases has been limited to the RAC1, CDC42, and RHOA proteins, a small subset of the RHO family.

    “The vast majority of investigation into RHO GTPases has been limited to the RAC1, CDC42, and RHOA proteins, a small subset of the RHO family.”

  • The paper relies on this without support.

    There is currently a limited number of small-molecule inhibitors with which to probe the activity of the DOCKs.

    “Finally, there is currently a limited number of small-molecule inhibitors with which to probe the activity of the DOCKs, such molecules would provide integral insight into their modulation for treating disease and provide starting points from which to design and discover new drugs.”
4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Figure 3 assigns PDB 6TGC to both autoinhibited and active complexes

    Minor

    Panel A identifies 6TGC as the autoinhibited DOCK2-ELMO1 complex, while panel B identifies the same structure as the active DOCK2-ELMO-RAC1 complex. Table 1 lists the DOCK2-ELMO1 structure as 6TGB and the RAC1-containing structure as 6TGC.

1 of 1

Cites

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Related

Authors
Thompson, A. P., Bitsina, C., Gray, J. L., von Delft, F., & Brennan, P. E.
Affiliations
University of Oxford (GB)
Corresponding author
Brennan, Paul E.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2021-01
Volume
296
Pages
100521
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/j.jbc.2021.100521
PMC
PMC8063744
OpenAlex
W3135782317
Semantic Scholar
f0a19f0334196a03e863689090848c0b327c7f20
Cited by
21
References
144
Citations by year
2026: 3 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 2
FWCI
1.08
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
RhoGEF, GDP dissociation, protein structure, cytoskeletal remodeling, small molecule inhibitors, chemical probes, drug discovery, brain disorders
MeSH terms
Protein Conformation, Catalytic Domain, GTP Phosphohydrolases, Rho Guanine Nucleotide Exchange Factors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-14.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-14.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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