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Cited by 40Protein Kinase Regulation and GTPase SignalingCellular transport and secretionProtein Tyrosine Phosphatases

The small GTPase RhoH is an atypical regulator of haematopoietic cells

Open access
Fueller, Florian, Kubatzky, Katharina F·2008·Cell Communication and Signaling
DOI 10.1186/1478-811x-6-6PMC PMC2565660
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Abstract

Rho GTPases are a distinct subfamily of the superfamily of Ras GTPases. The best-characterised members are RhoA, Rac and Cdc42 that regulate many diverse actions such as actin cytoskeleton reorganisation, adhesion, motility as well as cell proliferation, differentiation and gene transcription. Among the 20 members of that family, only Rac2 and RhoH show an expression restricted to the haematopoietic lineage.RhoH was first discovered in 1995 as a fusion transcript with the transcriptional repressor LAZ3/BCL6. It was therefore initially named translation three four (TTF) but later on renamed RhoH due to its close relationship to the Ras/Rho family of GTPases. Since then, RhoH has been implicated in human cancer as the gene is subject to somatic hypermutation and by the detection of RHOH as a translocation partner for LAZ3/BCL6 or other genes in human lymphomas. Underexpression of RhoH is found in hairy cell leukaemia and acute myeloid leukaemia.Some of the amino acids that are crucial for GTPase activity are mutated in RhoH so that the protein is a GTPase-deficient, so-called atypical Rho GTPase. Therefore other mechanisms of regulating RhoH activity have been described. These include regulation at the mRNA level and tyrosine phosphorylation of the protein's unique ITAM-like motif. The C-terminal CaaX box of RhoH is mainly a target for farnesyl-transferase but can also be modified by geranylgeranyl-transferase. Isoprenylation of RhoH and changes in subcellular localisation may be an additional factor to fine-tune signalling.Little is currently known about its signalling, regulation or interaction partners. Recent studies have shown that RhoH negatively influences the proliferation and homing of murine haematopoietic progenitor cells, presumably by acting as an antagonist for Rac1. In leukocytes, RhoH is needed to keep the cells in a resting, non-adhesive state, but the exact mechanism has yet to be elucidated. RhoH has also been implicated as a regulatory molecule in the NFkappaB, PI3 kinase and Map kinase pathways. The recent generation of RhoH knockout mice showed a defect in thymocyte selection and TCR signalling of thymic and peripheral T-cells. However, RhoH-deficient mice did not develop lymphomas or showed obvious defects in haematopoiesis.

AI snapshot

Written from the paper’s full text.

TL;DR

RhoH is a haematopoietic-specific atypical Rho GTPase that is GTPase-deficient and often acts as a negative regulator of Rac1, while also being required for T-cell receptor signalling via Zap70. In human cancers, RHOH is altered mainly by aberrant somatic hypermutation, translocation, or underexpression rather than by activating mutations.

Key findings

  • RhoH is atypical: it is GTPase-deficient, has a shortened Rho-specific insert of 7 amino acids instead of 13, and its C-terminal CKIF motif is modified in vitro by farnesyl-transferase and to a small extent by geranylgeranyl-transferase.
  • RHOH is targeted by aberrant somatic hypermutation in lymphoid cancers; in DLBCL, around 50% of cases had aberrant mutations for PIM1, PAX5, MYC and RHOH, and RHOH mutation frequency was 70% in primary CNS lymphoma versus 46% in DLBCL.
  • RhoH negatively regulates Rac1: RhoH-transduced cells showed reduced Rac1 activity, reduced polarised F-actin, and less migration to SDF-1α; high RhoH reduced myeloid colony growth by half and engraftment by approximately 50%.
  • RhoH is important for T-cell development: RhoH-deficient mice had approximately 60% lower thymus cellularity and 60% fewer double-negative thymocytes, with impaired positive selection and TCR signalling; RhoH’s ITAM-like motif binds Zap70 via tyrosines Y73 and Y83.

Methods

  • Narrative review of the literature on RhoH, including its structure, cancer alterations, and signalling, with the authors also presenting their own in vitro isoprenylation experiments for RhoH.
  • Data sources include published human cancer sample studies, mouse knockout models, and cell-line experiments; Table 1 summarises aberrant somatic hypermutation frequencies across lymphoid tumours.
  • Main analysis is qualitative synthesis; no systematic review, meta-analysis, or primary patient cohort is described.

Limitations

  • Stated in the paper: little is known about RhoH signalling, regulation, or interaction partners; the exact mechanism keeping leukocytes in a resting, non-adhesive state has yet to be elucidated; the significance of HEK293 experiments has not been corroborated in more physiologic setups; no comprehensive study of RhoH expression regulators exists; it has not been addressed whether RhoH is involved in T-cell malignancies, and it is not known whether RhoH modulates B-cell signalling.
  • Evident from the text: as a narrative review, it does not describe a systematic search or quality appraisal, and Table 1 combines heterogeneous studies with differing definitions of ASHM and sample sizes.
  • Evident from the text: several conclusions rely on overexpression/knockdown systems or non-haematopoietic cell lines, which may not fully reflect endogenous RhoH function.

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

Integrity signals

Registry

Crossref · 10.1186/1478-811x-6-6

Cites

73 of 73 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 114 cited sources checked · 19 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In vitro reconstitution of RhoH expression is sufficient to repress CD11c surface expression.

    “In vitro reconstitution of RhoH expression was sufficient to repress CD11c surface expression.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [55] Galiegue-Zouitina S, Delestre L, Dupont C, Troussard X, Shelley CS: Underexpression of RhoH in Hairy Cell Leukemia. Cancer Res. 2008, 68 (12): 4531-40. source
  • Premisecitation

    The lower RHOH mRNA expression in HCL is caused by transcriptional repression of the RHOH promoter.

    “The lower mRNA expression was found to be caused by transcriptional repression of the RHOH promoter [55].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [55] Galiegue-Zouitina S, Delestre L, Dupont C, Troussard X, Shelley CS: Underexpression of RhoH in Hairy Cell Leukemia. Cancer Res. 2008, 68 (12): 4531-40. source
  • Premisecitation

    Lymphocytes from HCL patients demonstrate approximately 3-4 fold lower RHOH mRNA expression compared to a variety of other lymphoid diseases.

    “Lymphocytes isolated from HCL patients demonstrate app. 3–4 fold lower RHOH mRNA expression compared to a variety of other diseases of the lymphoid system, such as Burkitt lymphoma, plasmocytoma or T-cell acute lymphoblastic leukaemia.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [55] Galiegue-Zouitina S, Delestre L, Dupont C, Troussard X, Shelley CS: Underexpression of RhoH in Hairy Cell Leukemia. Cancer Res. 2008, 68 (12): 4531-40. source

      The Results (page not provided) report 3.4-fold lower RhoH mRNA in HCL cell lines than in cell lines from the listed lymphoid diseases. The claim instead assigns that comparison to lymphocytes isolated from HCL patients. For patient-derived lymphocytes, the Results report a 5.2-fold reduction compared with healthy donors, not a 3–4-fold reduction compared with those diseases. (LLM, conf=0.93)

      Experimental — accuracy not yet measured
  • Premisecitation

    Overexpression of RhoH in hairy cell leukaemia reduces the transformation potential.

    “The recent finding that overexpression of RhoH in hairy cell leukaemia reduces the transformation potential [55] might stimulate a new interest in the functioning of RhoH on a molecular level.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [55] Galiegue-Zouitina S, Delestre L, Dupont C, Troussard X, Shelley CS: Underexpression of RhoH in Hairy Cell Leukemia. Cancer Res. 2008, 68 (12): 4531-40. source
  • Premisecitation

    RhoH reconstitution reduces transendothelial migration in a transwell assay.

    “In a transwell assay, the authors could demonstrate that RhoH reconstitution reduced transendothelial migration, a central process in the pathogenesis of the disease.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [55] Galiegue-Zouitina S, Delestre L, Dupont C, Troussard X, Shelley CS: Underexpression of RhoH in Hairy Cell Leukemia. Cancer Res. 2008, 68 (12): 4531-40. source
  • May combine two claims. 42
  • Classified as probably not a substantial claim. 1
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    RhoH is underexpressed in hairy cell leukaemia and acute myeloid leukaemia.

    “Two recent publications highlight the fact that RhoH is underexpressed in hairy cell leukaemia (HCL) and acute myeloid leukaemia (AML), respectively [55,56].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [55] Galiegue-Zouitina S, Delestre L, Dupont C, Troussard X, Shelley CS: Underexpression of RhoH in Hairy Cell Leukemia. Cancer Res. 2008, 68 (12): 4531-40. source
    • cites [56] Iwasaki T, Katsumi A, Kiyoi H, Tanizaki R, Ishikawa Y, Ozeki K, Kobayashi M, Abe A, Matsushita T, Watanabe T, Amano M, Kojima T, Kaibuchi K, Naoe T: Prognostic implication and biological roles of RhoH in acute myeloid leukaemia. Eur J Haematol. 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an in vivo xenograft model, RhoH reconstitution inhibits malignant progression and reduces tumour burden by 70%.

    “In an in vivo xenograft model, RhoH reconstitution leads to the inhibition of malignant progression. The tumour burden of the mice was reduced by 70% suggesting that elevated levels of RhoH protected the animals against mortality [55].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [55] Galiegue-Zouitina S, Delestre L, Dupont C, Troussard X, Shelley CS: Underexpression of RhoH in Hairy Cell Leukemia. Cancer Res. 2008, 68 (12): 4531-40. source

  • May combine two claims.

    Premisecitation

    Cells reconstituted with RhoH show decreased cell proliferation and homotypic and heterotypic adhesion.

    “Indeed, cells reconstituted with RhoH showed decreased cell proliferation and homotypic and heterotypic adhesion, respectively.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [55] Galiegue-Zouitina S, Delestre L, Dupont C, Troussard X, Shelley CS: Underexpression of RhoH in Hairy Cell Leukemia. Cancer Res. 2008, 68 (12): 4531-40. source

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

    Premisecitation

    RhoH is only found in vertebrates.

    “Phylogenetically, most Rho clusters seem to have already emerged in chordates, however, RhoH is only found in vertebrates [25].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Boureux A, Vignal E, Faure S, Fort P: Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol Biol Evol. 2007, 24 (1): 203-16. source

  • May combine two claims.

    Premisecitation

    RhoH activity is modulated by interaction with other Rho GTPases, transcriptional regulation, or phosphorylation rather than through classical GTPase cycling and effector modulation.

    “Its activity is modulated by interaction with other Rho GTPases [19,20], transcriptional regulation [19] or phosphorylation [21] rather than through the classical cycling process and modulation by effector proteins.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [19] Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B: The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol. 2002, 22 (4): 1158-71. source

      The Discussion (page unavailable) says RhoH is GTPase deficient, is unlikely to be regulated by nucleotide cycling, and may be regulated through mRNA expression; it also reports evidence of transcriptional regulation. It proposes competition with other Rho GTPases as a model, but does not establish that interaction with them regulates RhoH activity. The statement about phosphorylation is cited to [21], not this source; this paper mentions it only as a possible mechanism and does not establish the claim about effector-protein modulation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [20] Chae HD, Lee KE, Williams DA, Gu Y: Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells. Blood. 2008, 111 (5): 2597-605. source
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source

  • May combine two claims.

    Premisecitation

    PMA reduces endogenous RhoH transcripts in Jurkat cells after 60-80 min by 80% of baseline, while TNFα treatment does not regulate RhoH mRNA levels.

    “Li et al. tested a couple of stimuli on Jurkat cells and reported that PMA reduces endogenous RhoH transcripts after 60–80 min by 80% of the baseline level, while TNFα treatment did not act as a regulator of RhoH mRNA levels [19].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B: The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol. 2002, 22 (4): 1158-71. source

      The Results passage (page not provided) reports that PMA reduced endogenous RhoH mRNA in Jurkat cells by at least 80% from baseline at about 60–80 minutes. It also reports little overall change with TNF treatment, but notes a small, consistent transient reduction around 40–60 minutes; the claim's unqualified statement that TNFα did not regulate RhoH mRNA omits that exception. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a nucleotide dissociation assay, RhoH binds GTP rapidly but does not hydrolyse bound GTP to GDP.

    “In a nucleotide dissociation assay it was shown that although RhoH is able to bind GTP rapidly, it does not hydrolyse the bound GTP to GDP [19].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [19] Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B: The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol. 2002, 22 (4): 1158-71. source

      The Results (Fig. 8a–b) report that RhoH binds GTP rapidly and shows no detectable GTP hydrolysis. However, the nucleotide dissociation assay addressed binding and exchange; the lack of hydrolysis was established in a separate GTP hydrolysis assay. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Re-stimulation of cells on day 3 using anti-CD3 leads to a decrease of RhoH expression in Th1 cells, whereas no obvious changes occur in Th2 cells.

    “Re-stimulation of cells on day 3 using anti-CD3 led to a decrease of RhoH expression in Th1 cells whereas no obvious changes seemed to have occurred in the Th2 cells.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B: The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol. 2002, 22 (4): 1158-71. source

  • May combine two claims.

    Premisecitation

    RhoH overexpression does not induce activation of p38, JNK or Erk itself, but acts as a specific negative regulator for Rac- and RhoA-induced p38 activity.

    “Again, as with NFκB, RhoH overexpression did not induce activation of any of these proteins itself, but rather acted as a specific negative regulator for Rac and RhoA-induced p38 activity.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [19] Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B: The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol. 2002, 22 (4): 1158-71. source

      The Results (Fig. 4) show that RhoH expression did not activate p38, JNK, or ERK. The Results (Fig. 5) show that RhoH suppressed Rac1-induced p38 activation, but the RhoA experiment measured NFκB activation, not p38; the p38 experiment tested Rac1 and CDC42. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    RhoH is diffusely distributed in the cytoplasm, and RhoH overexpression causes no difference in morphology of PDGF-stimulated cells.

    “The authors describe RhoH to be diffusely distributed in the cytoplasm and they saw no difference in the morphology of PDGF stimulated cells in the presence or absence of RhoH overexpression [19].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B: The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol. 2002, 22 (4): 1158-71. source

  • May combine two claims.

    Interpretationcitation

    RhoH is an atypical Rho GTPase that is constitutively active and not regulated by classical GTP/GDP cycling.

    “The haematopoietic GTPase RhoH is an atypical family member of the Rho GTPases as it is constitutively active and not regulated through the classical cycling between GTP- and GDP-bound state.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [19] Li X, Bu X, Lu B, Avraham H, Flavell RA, Lim B: The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol. 2002, 22 (4): 1158-71. source

  • May combine two claims.

    Premisecitation

    In myeloid 32D cells transduced with RhoH, RhoH localises at the membrane, whereas deletion of the CaaX box leads to exclusively cytoplasmic localisation.

    “In myeloid 32D cells transduced with RhoH, RhoH was localised at the membrane while deletion of the CaaX box led to an exclusively cytoplasmic localisation.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Chae HD, Lee KE, Williams DA, Gu Y: Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells. Blood. 2008, 111 (5): 2597-605. source

      The Results (Figure 6B,C; page not provided) show that most RhoH in 32D myeloid progenitor cells was in membrane-containing fractions and that deleting its CKIF prenylation site abolished membrane localization. They do not support “exclusively cytoplasmic”: the C-terminally truncated mutant was also detected in the nuclear fraction (36% for RhoHdCT). (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    RhoH is modified in vitro by farnesyl-transferase and to a small extent by geranylgeranyl-transferase.

    “here we present biochemical data showing that RhoH is modified in vitro by farnesyl-transferase and to a small extent by geranylgeranyl-transferase (Figures 2A and 2B, respectively).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Overexpression of RhoH suppresses Rac1 activity, leading to increased apoptosis.

    “While overexpression of RhoH suppresses Rac1 activity thus leading to increased apoptosis (see following paragraph) [27]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Gu Y, Jasti AC, Jansen M, Siefring JE: RhoH, a hematopoietic-specific Rho GTPase, regulates proliferation, survival, migration, and engraftment of hematopoietic progenitor cells. Blood. 2005, 105 (4): 1467-75. source

  • May combine two claims.

    Premisecitation

    RhoH null mice are viable with no obvious defects in haematopoiesis, and RhoH is dispensable for development of myeloid, erythroid and B-cells.

    “RhoH null mice are viable with no obvious defects in haematopoiesis and RhoH seems to be dispensable for the development of myeloid, erythroid and B-cells [28].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Dorn T, Kuhn U, Bungartz G, Stiller S, Bauer M, Ellwart J, Peters T, Scharffetter-Kochanek K, Semmrich M, Laschinger M, Holzmann B, Klinkert WE, Straten PT, Kollgaard T, Sixt M, Brakebusch C: RhoH is important for positive thymocyte selection and T-cell receptor signaling. Blood. 2007, 109 (6): 2346-55. source

  • May combine two claims.

    Premisecitation

    RHOH contains one intronless coding region, two major non-coding exons, and three minor non-coding exons.

    “First of all, RHOH contains one intronless coding region, two major (1a and 1b) and three minor (X1, X2, X3) non-coding exons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Lahousse S, Smorowski AL, Denis C, Lantoine D, Kerckaert JP, Galiegue-Zouitina S: Structural features of hematopoiesis-specific RhoH/ARHH gene: high diversity of 5'-UTR in different hematopoietic lineages suggests a complex post-transcriptional regulation. Gene. 2004, 343 (1): 55-68. source

  • May combine two claims.

    Premisecitation

    The polymorphic form of PTLD rarely undergoes ASHM (12.5%), while the monomorphic form had ASHM in the majority of cases (66.7%).

    “While the polymorphic form of the disorder rarely undergoes ASHM (12.5%), the monomorphic form, representing a progression of the disease, had ASHM in the majority of cases investigated (66.7%) [52].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Vakiani E, Basso K, Klein U, Mansukhani MM, Narayan G, Smith PM, Murty VV, Dalla-Favera R, Pasqualucci L, Bhagat G: Genetic and phenotypic analysis of B-cell post-transplant lymphoproliferative disorders provides insights into disease biology. Hematol Oncol. 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The 2.2 kb RhoH transcript is expressed only in haematopoietic cells, with no detectable expression in other organ tissues.

    “In addition, it was found that the 2.2 kb RhoH transcript is expressed only in haematopoietic cells while no expression in other organ tissues was detectable [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Dallery E, Galiegue-Zouitina S, Collyn-d'Hooghe M, Quief S, Denis C, Hildebrand MP, Lantoine D, Deweindt C, Tilly H, Bastard C: TTF, a gene encoding a novel small G protein, fuses to the lymphoma-associated LAZ3 gene by t(3;4) chromosomal translocation. Oncogene. 1995, 10 (11): 2171-8.

  • May combine two claims.

    Premisecitation

    The mutation frequency for RHOH in monomorphic PTLD is 40%, nearly as high as in DLBCL.

    “The mutation frequency for RHOH in monomorphic PTLD was found to be 40% and therefore nearly as high as in DLBCL.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Vakiani E, Basso K, Klein U, Mansukhani MM, Narayan G, Smith PM, Murty VV, Dalla-Favera R, Pasqualucci L, Bhagat G: Genetic and phenotypic analysis of B-cell post-transplant lymphoproliferative disorders provides insights into disease biology. Hematol Oncol. 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    RhoH is a 191 amino acid protein and a novel homologue of the Ras family.

    “The initial characterisation showed that RhoH was a 191 amino acid containing protein and a novel homologue of the Ras family.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Dallery E, Galiegue-Zouitina S, Collyn-d'Hooghe M, Quief S, Denis C, Hildebrand MP, Lantoine D, Deweindt C, Tilly H, Bastard C: TTF, a gene encoding a novel small G protein, fuses to the lymphoma-associated LAZ3 gene by t(3;4) chromosomal translocation. Oncogene. 1995, 10 (11): 2171-8.

  • May combine two claims.

    Premisecitation

    RhoH is necessary for the production and survival or migration of T-cells.

    “On the other hand, animals showed impaired T-cell differentiation due to defective T-cell receptor signalling [21,28], as RhoH is necessary for the production and survival or migration of T-cells.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source
    • cites [28] Dorn T, Kuhn U, Bungartz G, Stiller S, Bauer M, Ellwart J, Peters T, Scharffetter-Kochanek K, Semmrich M, Laschinger M, Holzmann B, Klinkert WE, Straten PT, Kollgaard T, Sixt M, Brakebusch C: RhoH is important for positive thymocyte selection and T-cell receptor signaling. Blood. 2007, 109 (6): 2346-55. source

  • May combine two claims.

    Premisecitation

    Although Hodgkin lymphomas are targeted frequently by ASHM (55-80%), the RHOH gene is not mutated at high frequency.

    “Although Hodgkin lymphomas (HL) are targeted frequently by ASHM (55–80%), the RHOH gene is not mutated at high frequency [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Liso A, Capello D, Marafioti T, Tiacci E, Cerri M, Distler V, Paulli M, Carbone A, Delsol G, Campo E, Pileri S, Pasqualucci L, Gaidano G, Falini B: Aberrant somatic hypermutation in tumor cells of nodular-lymphocyte-predominant and classic Hodgkin lymphoma. Blood. 2006, 108 (3): 1013-20. source

  • May combine two claims.

    Premisecitation

    RhoH is GTPase-deficient and therefore belongs to the subset of atypical Rho GTPases.

    “However, like Rnd1, RhoE/Rnd3 and probably RhoBTB proteins, RhoH is GTPase-deficient [13] and therefore belongs to the subset of atypical GTPases.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Dallery E, Galiegue-Zouitina S, Collyn-d'Hooghe M, Quief S, Denis C, Hildebrand MP, Lantoine D, Deweindt C, Tilly H, Bastard C: TTF, a gene encoding a novel small G protein, fuses to the lymphoma-associated LAZ3 gene by t(3;4) chromosomal translocation. Oncogene. 1995, 10 (11): 2171-8.

  • May combine two claims.

    Premisecitation

    The LAZ3/BCL6-RHOH gene fusion places LAZ3/BCL6 under control of the RHOH promoter instead of expressing a fusion protein, and reciprocally places RHOH under control of the LAZ3/BCL6 promoter.

    “The breakpoint and gene orientation indicates that the gene fusion places LAZ3/BCL6 under the control of the RHOH promoter sequence instead of the expression of a fusion protein. Reciprocally, RHOH is placed under control of the LAZ3/BCL6 promoter.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Preudhomme C, Roumier C, Hildebrand MP, Dallery-Prudhomme E, Lantoine D, Lai JL, Daudignon A, Adenis C, Bauters F, Fenaux P, Kerckaert JP, Galiegue-Zouitina S: Nonrandom 4p13 rearrangements of the RhoH/TTF gene, encoding a GTP-binding protein, in non-Hodgkin's lymphoma and multiple myeloma. Oncogene. 2000, 19 (16): 2023-32. source

  • May combine two claims.

    Interpretationreasoning

    Low expression levels of RhoH might increase Rac1-induced protection from apoptosis, drug resistance and cause bad prognosis.

    “While overexpression of RhoH suppresses Rac1 activity thus leading to increased apoptosis (see following paragraph) [27], low expression levels of RhoH might increase Rac1-induced protection from apoptosis, drug resistance and cause bad prognosis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Gu Y, Jasti AC, Jansen M, Siefring JE: RhoH, a hematopoietic-specific Rho GTPase, regulates proliferation, survival, migration, and engraftment of hematopoietic progenitor cells. Blood. 2005, 105 (4): 1467-75. source

  • May combine two claims.

    Premisecitation

    RhoH has 27% identity to H-RAS and up to 45% identity with members of the Rho family.

    “While it had 27% identity to H-RAS it showed up to 45% identity with members of the Rho family.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Dallery E, Galiegue-Zouitina S, Collyn-d'Hooghe M, Quief S, Denis C, Hildebrand MP, Lantoine D, Deweindt C, Tilly H, Bastard C: TTF, a gene encoding a novel small G protein, fuses to the lymphoma-associated LAZ3 gene by t(3;4) chromosomal translocation. Oncogene. 1995, 10 (11): 2171-8.

  • May combine two claims.

    Premisecitation

    RhoH-deficient mice do not develop lymphomas and have no obvious defects in HSC maintenance, but show impaired T-cell differentiation attributed to defective T-cell receptor signalling.

    “RhoH-deficient mice did not develop lymphomas and had no obvious defects in HSC maintenance, but they showed impaired T-cell differentiation attributed to defective T-cell receptor signalling.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source
    • cites [28] Dorn T, Kuhn U, Bungartz G, Stiller S, Bauer M, Ellwart J, Peters T, Scharffetter-Kochanek K, Semmrich M, Laschinger M, Holzmann B, Klinkert WE, Straten PT, Kollgaard T, Sixt M, Brakebusch C: RhoH is important for positive thymocyte selection and T-cell receptor signaling. Blood. 2007, 109 (6): 2346-55. source

  • May combine two claims.

    Premisecitation

    RhoH acts as a positive regulatory factor for thymocyte selection and T-cell receptor signalling.

    “Two groups independently showed that RhoH acts as a positive regulatory factor for thymocyte selection and T-cell receptor signalling [21,28].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source
    • cites [28] Dorn T, Kuhn U, Bungartz G, Stiller S, Bauer M, Ellwart J, Peters T, Scharffetter-Kochanek K, Semmrich M, Laschinger M, Holzmann B, Klinkert WE, Straten PT, Kollgaard T, Sixt M, Brakebusch C: RhoH is important for positive thymocyte selection and T-cell receptor signaling. Blood. 2007, 109 (6): 2346-55. source

  • May combine two claims.

    Premisecitation

    RhoH-deficient mice have abnormally low levels of T-lymphocytes and thymus cellularity approximately 60% lower than control animals, due to reduced proliferative cell expansion.

    “RhoH-deficient mice were found to have abnormally low levels of T-lymphocytes and the cellularity of their thymus was app. 60% lower than in control animals, due to reduced proliferative cell expansion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source

  • May combine two claims.

    Premisecitation

    High RhoH expression reduces growth and formation of myeloid colonies compared to control cells by half, due to an increase in apoptotic cells.

    “In response to stem cell factor (SCF), high RhoH expression levels reduced growth and formation of myeloid colonies compared to control cells by half, due to an increase in apoptotic cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Gu Y, Jasti AC, Jansen M, Siefring JE: RhoH, a hematopoietic-specific Rho GTPase, regulates proliferation, survival, migration, and engraftment of hematopoietic progenitor cells. Blood. 2005, 105 (4): 1467-75. source

  • May combine two claims.

    Interpretationcitation

    RhoH contains a novel ITAM-like motif that serves as a binding site for Zap70, which is then shuttled to the T-cell receptor complex where it triggers activation of the LAT signalosome.

    “RhoH contains a novel ITAM-like motif that serves as a binding site for Zap70, which is then shuttled to the T-cell receptor complex where it serves as a crucial molecule to trigger activation of the LAT signalosome.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source
    • cites [28] Dorn T, Kuhn U, Bungartz G, Stiller S, Bauer M, Ellwart J, Peters T, Scharffetter-Kochanek K, Semmrich M, Laschinger M, Holzmann B, Klinkert WE, Straten PT, Kollgaard T, Sixt M, Brakebusch C: RhoH is important for positive thymocyte selection and T-cell receptor signaling. Blood. 2007, 109 (6): 2346-55. source

  • May combine two claims.

    Premisecitation

    RhoH-deficient mice show impaired development of thymocytes and reduced TCR signalling due to inefficient recruitment of Zap70.

    “RhoH-deficient mice showed an impaired development of thymocytes and reduced TCR signalling due to inefficient recruitment of Zap70 [21,28].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source
    • cites [28] Dorn T, Kuhn U, Bungartz G, Stiller S, Bauer M, Ellwart J, Peters T, Scharffetter-Kochanek K, Semmrich M, Laschinger M, Holzmann B, Klinkert WE, Straten PT, Kollgaard T, Sixt M, Brakebusch C: RhoH is important for positive thymocyte selection and T-cell receptor signaling. Blood. 2007, 109 (6): 2346-55. source

  • May combine two claims.

    Premisecitation

    In RhoH-deficient mice, the number of double negative thymocytes is reduced by 60%, indicating disturbed development between DN and DP stages; this is reflected in an elevated number of CD44- CD25+ DN3 cells.

    “In mutant mice, the number of double negative thymocytes was reduced by 60%, indicating that the development between double negative (DN) to double positive (DP) stages was disturbed; this was also reflected in an elevated number of CD44- CD25+ DN3 cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source

  • May combine two claims.

    Premisecitation

    Knockdown of RhoH stimulates proliferation and survival, as well as SDF-1α mediated migration in vivo.

    “Conversely, a knockdown of RhoH stimulated proliferation and survival, as well as SDF-1α mediated migration in vivo [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Gu Y, Jasti AC, Jansen M, Siefring JE: RhoH, a hematopoietic-specific Rho GTPase, regulates proliferation, survival, migration, and engraftment of hematopoietic progenitor cells. Blood. 2005, 105 (4): 1467-75. source

  • May combine two claims.

    Premisecitation

    Although peripheral thymocytes express the TCR complex at normal levels, anti-CD3ε stimulation triggers only a reduced proliferative response, suggesting down-regulation occurs downstream of the TCR complex.

    “Although peripheral thymocytes expressed the TCR complex at normal levels, anti-CD3ε stimulation triggered only a reduced proliferative response suggesting that the down-regulation occurred downstream of the TCR complex [21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source

  • May combine two claims.

    Premisecitation

    RhoH-transduced cells show reduced Rac1 activity, reduced polarised cortical F-actin staining, and less cell migration in response to SDF-1α.

    “RhoH-transduced cells, however, showed reduced Rac1 activity, reduced polarised cortical F-actin staining and less cell migration in response to SDF-1α [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Gu Y, Jasti AC, Jansen M, Siefring JE: RhoH, a hematopoietic-specific Rho GTPase, regulates proliferation, survival, migration, and engraftment of hematopoietic progenitor cells. Blood. 2005, 105 (4): 1467-75. source

  • May combine two claims.

    Premisecitation

    The basal level of Rac1 activity is elevated in RhoH-deficient T-cells, suggesting RhoH is an antagonist for Rac1 activity by inhibiting basal Rac1 activity.

    “However, the authors noted that the basal level of Rac1 activity seemed to be elevated in RhoH-deficient T-cells, suggesting once more that RhoH is an antagonist for Rac1 activity by inhibiting basal Rac1 activity [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Dorn T, Kuhn U, Bungartz G, Stiller S, Bauer M, Ellwart J, Peters T, Scharffetter-Kochanek K, Semmrich M, Laschinger M, Holzmann B, Klinkert WE, Straten PT, Kollgaard T, Sixt M, Brakebusch C: RhoH is important for positive thymocyte selection and T-cell receptor signaling. Blood. 2007, 109 (6): 2346-55. source

  • May combine two claims.

    Premisecitation

    Injection of irradiated mice with bone marrow cells transduced with RhoH confirmed the crucial role of RhoH in thymocyte maturation and TCR signalling, since reconstitution of RhoH compensated for the defects of RhoH-deficient mice.

    “Injection of irradiated mice with bone marrow cells transduced with RhoH confirmed the crucial role of RhoH in thymocyte maturation and TCR signalling since reconstitution of RhoH compensated for the defects of RhoH-deficient mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source

  • May combine two claims.

    Premisecitation

    RhoH negatively influences proliferation, migration and engraftment of haematopoietic bone marrow derived progenitor cells.

    “Supporting the theory that RhoH acts as a negative regulator of Rac signalling and other signalling cascades, it was found that RhoH negatively influences proliferation, migration and engraftment of haematopoietic bone marrow derived progenitor cells [27].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Gu Y, Jasti AC, Jansen M, Siefring JE: RhoH, a hematopoietic-specific Rho GTPase, regulates proliferation, survival, migration, and engraftment of hematopoietic progenitor cells. Blood. 2005, 105 (4): 1467-75. source

  • May combine two claims.

    Premisecitation

    Decrease of RhoH expression activates LFA-1, rendering leukocytes adhesive and active.

    “By searching for a deregulated LFA-1 phenotype using a retroviral insertion mutagenesis approach, Cherry et al. found that a decrease of RhoH expression activated LFA-1, thus rendering the leukocytes adhesive and therefore active.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Cherry LK, Li X, Schwab P, Lim B, Klickstein LB: RhoH is required to maintain the integrin LFA-1 in a nonadhesive state on lymphocytes. Nat Immunol. 2004, 5 (9): 961-7. source

  • May combine two claims.

    Interpretationreasoning

    RhoH has no transforming potential itself, but rather is an important regulatory molecule that must be expressed in order to protect the cell from malignant transformation.

    “This indicates that RhoH has no transforming potential itself, but rather is an important regulatory molecule that must be expressed in order to protect the cell from malignant transformation.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Interpretationcitation

    RhoH acts as a shuttle for Zap70, interacting with cytoplasmic Zap70 in the absence of antigen presenting cells and moving to the plasma membrane upon activation.

    “Subcellular fractionation and immunofluorescence staining showed that RhoH acts as a shuttle for Zap70 and interacts with the pool of Zap70 molecules localised in the cytoplasm in the absence of antigen presenting cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source

  • May combine two claims.

    Premisecitation

    In RhoH-deficient mice, expression of positive selection markers CD5 and CD69 is reduced, suggesting RhoH plays a role in thymocyte positive selection.

    “In RhoH-deficient mice the expression of these markers was reduced, suggesting that RhoH plays a role in thymocyte positive selection.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, Williams DA: RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol. 2006, 7 (11): 1182-90. source
43 of 43

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 reverses the colour key for RHOH alterations

    Minor

    The text assigns blue to translocations and green to somatic hypermutation, while the Figure 3 caption assigns those colours the opposite meanings.

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Authors
Fueller, F., & Kubatzky, K. F.
Affiliations
  • University of Freiburg (DE)
  • Heidelberg University (DE)
Corresponding author
Kubatzky, Katharina F
ORCID
Kubatzky, Katharina F
Venue
Cell Communication and Signaling
Publisher
Springer Science and Business Media LLC
Published
2008-09-29
Volume
6
Issue
1
Pages
6-6
ISSN
1478-811X (ISSN-L)
DOI
10.1186/1478-811x-6-6
PMC
PMC2565660
OpenAlex
W2058566040
Semantic Scholar
a29e0263aeeb975d14c7a7d6df1fd00d23e8c6b8
Cited by
40
References
73
Citations by year
2025: 4 · 2024: 4 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 1 · 2014: 1 · 2013: 2 · 2012: 13
FWCI
0.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Communication and Signaling (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft
  • Universität Heidelberg
  • Université de Fribourg
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 Tyrosine Phosphatases
Keywords
RhoH, Rho GTPases, hematopoietic cells, leukocyte adhesion, thymic selection, T cell receptor signaling, NF-κB signaling, PI3 kinase pathway, MAPK signaling, farnesyltransferase, geranylgeranyltransferase, CAAX box, tyrosine phosphorylation

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