New Partners for Ena/VASP

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Science's STKE  19 Oct 2004:
Vol. 2004, Issue 255, pp. tw370
DOI: 10.1126/stke.2552004tw370


The Ena/VASP family proteins are important regulators of the cytoskeleton that are recruited to sites of actin remodeling during cell adhesion, polarization, and migration. Within locations such as focal adhesions and lamellipodia, Ena/VASP proteins alter local actin dynamics through their interactions with actin and profilin, as well as through their associations with proteins that bind to their proline-rich protein interaction domain, EVH1. Less well understood is how Ena/VASP proteins locally alter actin dynamics in response to specific cell signals. Two related adaptor proteins have now been identified as Ena/VASP binding partners that could provide the link between localized membrane-based signaling events and cytoskeletal remodeling. Krause et al. have determined that mammalian Lamellipodin (Lpd), whose C. elegans ortholog, Mig-10, controls neuronal migration, binds to Ena/VASP proteins. Lpd and Ena/VASP proteins colocalized at the tips of lamellipodia in a variety of mammalian cell types and were isolated in a protein complex from primary cortical neurons. However, Lpd localization did not depend on the presence of Ena/VASP. Rather, Lpd directed Ena/VASP protein localization, a recruitment dependent on the EVH1-binding motifs within Lpd. A Ras-association (RA) and lipid-binding PH domain in Lpd were required for targeting to the leading edge of lamellipodia. The PH domain specifically associated with PI(3,4)P2, a phosphoinositide involved in cell polarization. Overexpression of Lpd also increased lamellipodia protrusion velocity in fibroblasts, an effect that required Ena/VASP expression. Knockdown of Lpd by RNA interference reduced actin polymerization in lamellipodia and impaired lamellipodia formation. Similar in Lpd, Rap1-interacting adaptor molecule (RIAM) was identified by Lafuente et al. as another Ena/VASP interacting protein. Both RIAM and Lpd exhibit similar protein domain structure, comprising a new family of adaptor proteins called MRL (Mig-10/RIAM/Lpd). In activated T cells, RIAM associated with activated Rap1, a Ras superfamily member that localizes to the plasma membrane to control cell adhesion and spreading. RIAM was also required for activated Rap1 to localize to the plasma membrane and stimulate integrin-mediated adhesion in T cells. RIAM was distributed throughout the leading edge of lamellipodia, and its overexpression induced cell adhesion. Knockdown of RIAM expression by RNA interference reduced the cellular content of polymerized F actin and adhesion. Although RIAM and Lpd are both found in the leading edge of lamellipodia, Lpd did not bind to activated Rap1 and did not localize to focal adhesions, which suggests that the two adaptors may couple Ena/VASP to distinct signaling pathways within similar subcellular locations. The two adaptor proteins may integrate signals from both phosphoinositides and Ras superfamily proteins and direct actin through association with Ena/VASP.

M. Krause, J. D. Leslie, M. Stewart, E. M. Lafuente, F. Valderrama, R. Jagannathan, G. A. Strasser, D. A. Rubinson, H. Liu, M. Way, M. B. Yaffe, V. A. Boussiotis, F. B. Gertler, Lamellipodin, an Ena/VASP ligand, is implicated in the regulation of lamellipodial dynamics. Devel. Cell 7, 571-583 (2004). [Online Journal]

E. M. Lafuente, A. A. F. L. van Puijenbroek, M. Krause, C. V. Carman, G. J. Freeman, A. Berezovskaya, E. Constantine, T. A. Springer, F. B. Gertler, V. A. Boussiotis, RIAM, an Ena/VASP and profilin ligand, interacts with RAP1-GTP and mediates Rap1-induced adhesion. Devel. Cell 7, 585-595 (2004). [Online Journal]

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