c-Abl interacts with the WAVE2 signaling complex to induce membrane ruffling and cell spreading.
The Wiskott-Aldrich syndrome-related protein WAVE2 promotes Arp2/3-dependent actin polymerization downstream of Rho-GTPase activation. The Abelson-interacting protein-1 (Abi-1) forms the core of the WAVE2 complex and is necessary for proper stimulation of WAVE2 activity. Here we have shown that the Abl-tyrosine kinase interacts with the WAVE2 complex and that Abl kinase activity facilitates interaction between Abl and WAVE2 complex members. We have characterized various interactions between Abl and members of the WAVE2 complex and revealed that Abi-1 promotes interaction between Abl and WAVE2 members. We have demonstrated that Abl-dependent phosphorylation of WAVE2 is necessary for its activation in vivo, which is highlighted by the findings that RNA interference of WAVE2 expression in Abl/Arg-/- cells has no additive effect on the amount of membrane ruffling. Furthermore, Abl phosphorylates WAVE2 on tyrosine 150, and WAVE2-deficient cells rescued with a Y150F mutant fail to regain their ability to ruffle and form microspikes, unlike cells rescued with wild-type WAVE2. Together, these data show that c-Abl activates WAVE2 via tyrosine phosphorylation to promote actin remodeling in vivo and that Abi-1 forms the crucial link between these two factors.
Stuart
Jeremy R
JR
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Gonzalez
Francis H
FH
Kawai
Hidehiko
H
Yuan
Zhi-Min
ZM
D016475:3T3 Cells; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D004843:Epistasis, Genetic; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000737:chemistry*
C120152:WASF2 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D016315:Proto-Oncogene Proteins c-abl; D020741:rho GTP-Binding Proteins