Activation of the WAVE Complex by Coincident Signals Controls Actin Assembly
Open accessAbstract
WAVE proteins link upstream signals to actin nucleation by activating the Arp2/3 complex and are at the core of regulatory pathways driving membrane protrusion. They are found in heteropentameric complexes whose role in regulating WAVE function is presently unclear. Here we demonstrate that purified native WAVE complexes are basally inactive; previous reports of constitutive activity are artifacts of in vitro manipulation. Further, the native complexes are not activated by Rac alone. Activation of the WAVE2 complex requires simultaneous interactions with prenylated Rac-GTP and acidic phospholipids, as well as a specific state of phosphorylation. Together these signals promote full activation in a highly cooperative process on the membrane surface, by inducing an allosteric change in the complex rather than by simple recruitment or by dissociation of the subunits. These results explain how the WAVE complex can integrate coincident signals to promote localized actin nucleation during cell motility.
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Acidic phospholipids such as PIP3 or PI(4,5)P2 bind to the basic surface of WAVE2 complexes, enhancing WAVE2 complex activation via prenylated Rac1.
“Acidic phospholipids such as phosphatidylinositol (3,4,5)-triphosphate (PIP3) or PI(4,5)P2 bind to the basic surface of WAVE2 complexes, enhancing WAVE2 complex activation via prenylated Rac120 (Fig. 2).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [20]
The Results sections on cooperative activation and binding report that PIP3 and PI(4,5)P2 support WAVE2-complex activation with prenylated Rac1-GTP, and that acidic lipids bind the complex. They do not identify a basic surface of the complex as the lipid-binding site; the copy also specifies the GTP-bound state of Rac1, which the claim omits. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredActivation of the native WAVE1 complex isolated from the bovine brain was not affected by prenylated Rac1 or PIP2, indicating potential differences in the regulation of the WAVE1 and WAVE2 complexes.
“However, the activation of the native WAVE1 complex isolated from the bovine brain was not affected by prenylated Rac1 or PIP2, indicating potential differences in the regulation of the WAVE1 and WAVE2 complexes20.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [20]
The Results report that native WAVE1 purified from bovine brain was not activated by Rac1-GTP. They also say that conditions using Rac and PIP3 liposomes that activated WAVE2 did not activate WAVE1, suggesting possible differences in regulation, while noting that WAVE1 purification might instead have lost important modifications. The cited passage does not establish that PIP2 was tested on WAVE1; it specifies PIP3. (LLM, conf=0.88)
Experimental — accuracy not yet measuredWAVE proteins exist as heteropentameric complexes together with regulatory proteins including CYFIP, NCKAP, ABI and BRK1 (specifically NCKAP1/1L, CYFIP1/2, ABI1/2/3, and BRK1).
“WAVE proteins exist as heteropentameric complexes together with regulatory proteins, including CYFIP, NCKAP, ABI and BRK1.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [20]
The native full-length WAVE2 complex was successfully activated by the cooperative actions of prenylated RAC-GTP, acidic phospholipids and phosphorylation.
“The native full-length WAVE2 complex was successfully activated by the cooperative actions of prenylated RAC-GTP, acidic phospholipids and phosphorylation20.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [20]
Several studies have used intact WAVE complexes isolated from the brain or cells.
“In fact, several studies have used intact WAVE complexes isolated from the brain or cells19,20,22,179.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [20]
Compared with their paralogs, WAVE1, CYFIP2, NCKAP1 and ABI2 are relatively abundant in the brain.
“Compared with their paralogs, WAVE1, CYFIP2, NCKAP1 and ABI2 are relatively abundant in the brain19,20,22 (Fig. 1).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [20]
The Results section (‘Native WAVE complexes are basally inactive’) says the authors purified WAVE1 complexes from bovine brain and notes that WAVE1 and WAVE2 have different expression patterns. It does not compare brain abundance with paralogs for WAVE1, CYFIP2, NCKAP1, or ABI2; searches for brain expression and those subunits found no such comparison. Page numbers were not available in our copy. (LLM, conf=0.75)
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The WAVE complex in developmental and adulthood brain disorders
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- Authors
- Lebensohn, A. M., & Kirschner, M. W.
- Affiliations
- Harvard University (US)
- Corresponding author
- Kirschner, Marc W.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 36
- Issue
- 3
- Pages
- 512-524
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC2818508
- OpenAlex
- W1967248496
- Cited by
- 263
- References
- 1
- Citations by year
- 2026: 13 · 2025: 9 · 2024: 6 · 2023: 9 · 2022: 13 · 2021: 22 · 2020: 15 · 2019: 19 · 2018: 9 · 2017: 10 · 2016: 13 · 2015: 13 · 2014: 23 · 2013: 25 · 2012: 19
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM026875)
- 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 › Cellular transport and secretion
- Keywords
- WAVE complex, WAVE2, Arp2/3 complex, actin nucleation, actin assembly, Rac GTPase, anionic phospholipids, allosteric activation, signal integration, cell motility, membrane protrusions, protein phosphorylation
- MeSH terms
- Actins, Amino Acid Sequence, Animals, Cattle, Cell Membrane, Cell Movement, Humans, Molecular Sequence Data, Phospholipids, Phosphorylation, Swine, Blotting, Western, Signal Transduction, Oncogene Proteins, Microscopy, Confocal, rac GTP-Binding Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Wiskott-Aldrich Syndrome Protein Family, Prenylation
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