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Protein A002549
Author-entered Data
V1.0, Peer Reviewed
Published 1 Sep 2012
Automated Data
Not Reviewed
As At Publication
Automated Data
Not Reviewed
Latest from 6 Jun 2014

UCSD Molecule Pages
Published online: 1 Sep 2012 | doi:10.6072/H0.MP.A002549.01


Basis Sequence: Mouse

Tadaomi Takenawa1, Shiro Suetsugu2, Daisuke Yamazaki3, Shusaku Kurisu1

1Division of Lipid Biochemistry, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Hyogo 650-0017, JP. 2Laboratory of Membrane and Cytoskeleton Dynamics, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, JP. 3Division of Membrane Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Hyogo 650-0017, JP.

Correspondence should be addressed to Tadaomi Takenawa:

WASP family verprolin-homologous protein 2 (WAVE2, also called WASF2) was originally identified by its sequence similarity at the carboxy-terminal VCA (verprolin, cofilin/central, acidic) domain with Wiskott-Aldrich syndrome protein (WASP) and N-WASP (neural WASP). In mammals, WAVE2 is ubiquitously expressed, and its two paralogs, WAVE1 (also called suppressor of cAMP receptor 1, SCAR1) and WAVE3, are predominantly expressed in the brain. The VCA domain of WASP and WAVE family proteins can activate the actin-related protein 2/3 (Arp2/3) complex, a major actin nucleator in cells. Proteins that can activate the Arp2/3 complex are now collectively known as nucleation-promoting factors (NPFs), and the WASP and WAVE families are a founding class of NPFs.

The WAVE family has an amino-terminal WAVE homology domain (WHD domain, also called the SCAR homology domain, SHD) followed by the proline-rich region that interacts with various Src-homology 3 (SH3) domain proteins. The VCA domain located at the C-terminus. WAVE2, like WAVE1 and WAVE3, constitutively forms a huge heteropentameric protein complex (the WANP complex), binding through its WHD domain with Abi-1 (or its paralogs, Abi-2 and Abi-3), HSPC300 (also called Brick1), Nap1 (also called Hem-2 and NCKAP1), Sra1 (also called p140Sra1 and CYFIP1; its paralog is PIR121 or CYFIP2).

The WANP complex is recruited to the plasma membrane by cooperative action of activated Rac GTPases and acidic phosphoinositides. Activated Rac indirectly associates with WAVE2 through Sra1 and/or insulin receptor tyrosine kinase substrate p53 (IRSp53). These interactions link Rac activation and the membrane recruitment of WAVE2. How acidic membrane phosphoinositides, including phosphatidylinositol-(4,5)-bisphosphate (PtdIns(4,5)P2) and phosphatidylinositol-(3,4,5)-triphosphate (PtdIns(3,4,5)P3), associate with the WANP complex is still unclear. However, purified monomeric WAVE2 binds directly to PtdIns(3,4,5)P3, and weakly to PtdIns(4,5)P2, through a basic amino acid cluster located just C-terminal to the WHD domain, suggesting that the interaction between the WANP complex and acidic phosphoinositides is mediated by WAVE proteins.

Binding of Rac and acidic phosphoinositides is also thought to activate the WANP complex at the plasma membrane. Cooperatively, tyrosine phosphorylation and serine/threonine phosphorylation of WAVE2 contribute to its activation. Although the precise mechanism of WANP complex activation remains to be elucidated, a plausible explanation is that the VCA domain, which is likely to be conformationally inhibited in the WANP complex, becomes released from the WANP complex following activation. The activated VCA domain can then simultaneously interact with the Arp2/3 complex and monomeric actin, leading to formation of an actin-nucleus-like core that is necessary to initiate actin polymerization.

Therefore, the WAVE family proteins mediate signals from Rac to the Arp2/3 to polymerize branched actin filaments in the vicinity of the plasma membrane enriched with PtdIns(4,5)P2 and PtdIns(3,4,5)P3. This signaling underlies Rac-induced formation of lamellipodial actin networks.

Alternative names for this molecule: Scar-2; Scar2; WAS protein family, member 2; Wasf-2; Wasf2; WASF2; Wave-2; WAVE2

Transition Network Graph This molecule exists in 33 states and has 33 transitions between these states.

[map] View high resolution network map