WAVE regulatory complex
Open accessAbstract
Dynamic rearrangement of the actin cytoskeleton drives a myriad of processes in eukaryotic cells, such as cell migration and vesicle trafficking, and its dysregulation is deeply associated with various diseases, including cancer, immune deficiency, and neurological disorders. Members of the Wiskott-Aldrich syndrome protein (WASP) family, including WASP, N-WASP, WAVE, WASH, WHAMM, JMY, and the recently identified WHIMP, are ubiquitous regulators of actin dynamics. Although each WASP-family protein uses a different regulatory mechanism and participates in distinct cellular processes, they all act by integrating various upstream signals and transmitting them to their carboxy-terminal WCA (WH2-central-acidic, where WH2 stands for WASP homology 2) domain. This domain stimulates the actin nucleation activity of the Arp2/3 complex to promote the formation of new filaments from existing ones, creating branched actin networks that are crucial for dynamic deformations of membranes.
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HEM1 protein modeling suggested that the affected amino acids, despite their locations on distant exons, cluster in a hotspot that is likely crucial for conformational stability.
“HEM1 protein modeling suggested that the affected amino acids, despite their locations on distant exons, cluster in a hotspot that is likely crucial for conformational stability [16].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [16]
The “Implications in diseases” section says Hem1 has one mutation hot spot and that most Hem1 mutations appear to disrupt its structure. It also describes WRC mutations clustering spatially despite being distant in the protein’s primary sequence, but does not establish that the affected Hem1 amino acids are encoded by distant exons; it notes an exception to the structural-disruption pattern. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHEM1 expression is restricted to hematopoietic cells and HEM2 is expressed in all other tissues.
“HEM1 expression is restricted to hematopoietic cells and its counterpart, HEM2, is expressed in all other tissues [16].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [16]
In “Biological/organismic functions” (page unavailable), the paper describes Hem1 as tissue-specific to hematopoietic cells and Nap1 as ubiquitously expressed. “Composition and assembly” identifies Nap1 as Hem2. This supports the broad expression contrast, but not the claim that Hem2 is expressed only in tissues other than hematopoietic cells; ubiquitous expression does not imply that exclusion. (LLM, conf=0.86)
Experimental — accuracy not yet measuredUpon cellular stimulation, the WRC is recruited to the plasma membrane to communicate with central signaling molecules including PI3K, MAPK, FAK, AKT, and PKC; these effectors govern activation, growth, proliferation, and survival.
“Upon cellular stimulation, the WRC is recruited to the plasma membrane to communicate with central signaling molecules including phosphatidylinositol-3 kinases (PI3K), mitogen-activated protein kinases (MAPK), focal adhesion kinase (FAK), protein kinase B/AKT, and protein kinase C. These effectors subsequently govern activation, growth, proliferation, and survival [16, 24].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [16]
The Regulation mechanisms section (page unavailable) says the WRC moves to the plasma membrane during activation and interacts with signaling ligands. It does not identify PI3K, MAPK, FAK, AKT, and PKC as WRC partners or say that these effectors subsequently govern activation, growth, proliferation, and survival. Its mention of PIP3 does not establish an interaction with PI3K. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTwo distinct RAC1-binding sites on CYFIP1/2 and a recently discovered ARF1-binding site on HEM1/2 cooperatively activate the WRC.
“Two distinct RAC1-binding sites on CYFIP1/2 and a recently discovered ARF1-binding site on HEM1/2 cooperatively activate the WRC [16, 17].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [16]
The Composition and assembly section identifies Sra1 as CYFIP1 and its ortholog as CYFIP2; Regulation mechanisms describes two Rac1-binding sites on Sra1. It says Arf1 might cooperate with Rac1, but does not identify a recently discovered Arf1-binding site on HEM1/2 and says how the GTPases cooperate is mostly unknown. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
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Cites
No references could be resolved yet.
Research works printed but not linked: 15
- [1]Begemann A, Sticht H, Begtrup A, Vitobello A, Faivre L, Banka S, Alhaddad B, Asadollahi R, Becker J, Bierhals T, (2020). New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics. Genet Med. PMC7935717 33149277
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- [6]Fort L, Batista JM, Thomason PA, Spence HJ, Whitelaw JA, Tweedy L, Greaves J, Martin KJ, Anderson KI, Brown P, (2018). Fam49/CYRI interacts with Rac1 and locally suppresses protrusions. Nat Cell Biol 20, 1159– 1171. 30250061 PMC6863750
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Cited by
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HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions
Cook, S., Lenardo, M. J., & Freeman, A. F. (2022) · Journal of Clinical Immunology · doi:10.1007/s10875-022-01327-0 · Cited by 24 · see citing works
- Authors
- Rottner, K., Stradal, T. E. B., & Chen, B.
- Affiliations
- Helmholtz Centre for Infection Research (DE)
- Iowa State University (US)
- Corresponding author
- Rottner, Klemens
- Chen, Baoyu
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2021-05
- Volume
- 31
- Issue
- 10
- Pages
- R512-R517
- ISSN
- 0960-9822 (ISSN-L)
- PMC
- PMC8882368
- OpenAlex
- W3164313383
- Cited by
- 116
- References
- 0
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 22 · 2023: 30 · 2022: 15 · 2021: 5 · 2020: 1
- FWCI
- 9.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 391 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Iowa State University Digital Repository (Iowa State University) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute of General Medical Sciences (R35GM128786)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- WAVE regulatory complex, WASP family proteins, actin cytoskeleton, Arp2/3 complex, actin nucleation, WH2 domain, branched actin networks, membrane deformation, N-WASP, water, sanitation and hygiene, JMY
- MeSH terms
- Actins, Cytoskeleton, Actin Cytoskeleton, Wiskott-Aldrich Syndrome Protein Family, Wiskott-Aldrich Syndrome Protein, Actin-Related Protein 2-3 Complex
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