The Cdc42 Effector IRSp53 Generates Filopodia by Coupling Membrane Protrusion with Actin Dynamics

The Cdc42 effector IRSp53 is a strong inducer of filopodia formation and consists of an Src homology domain 3 (SH3), a potential WW-binding motif, a partial-Cdc42/Rac interacting binding region motif, and an Inverse-Bin-Amphiphysins-Rvs (I-BAR) domain.We show that IRSp53 interacts directly with neuronal Wiskott-Aldrich syndrome protein (N-WASP) via its SH3 domain and furthermore that N-WASP is required for filopodia formation as IRSp53 failed to induce filopodia formation in N-WASP knock-out (KO) fibroblasts. IRSp53-induced filopodia formation can be reconstituted in N-WASP KO fibroblasts by full-length N-WASP, by N-WASPΔWA (a mutant unable to activate the Arp2/3 complex), and by N-WASPH208D (a mutant unable to bind Cdc42). IRSp53 failed to induce filopodia in mammalian enabled (Mena)/VASP KO cells, and N-WASP failed to induce filopodia when IRSp53 was knocked down with RNA interference. The IRSp53 I-BAR domain alone induces dynamic membrane protrusions that lack actin and are smaller than normal filopodia (“partial-filopodia”) in both wild-type N-WASP and N-WASP KO cells. We propose that IRSp53 generates filopodia by coupling membrane protrusion through its I-BAR domain with actin dynamics through SH3 domain binding partners, including N-WASP and Mena. The Cdc42 effector IRSp53 is a strong inducer of filopodia formation and consists of an Src homology domain 3 (SH3), a potential WW-binding motif, a partial-Cdc42/Rac interacting binding region motif, and an Inverse-Bin-Amphiphysins-Rvs (I-BAR) domain.We show that IRSp53 interacts directly with neuronal Wiskott-Aldrich syndrome protein (N-WASP) via its SH3 domain and furthermore that N-WASP is required for filopodia formation as IRSp53 failed to induce filopodia formation in N-WASP knock-out (KO) fibroblasts. IRSp53-induced filopodia formation can be reconstituted in N-WASP KO fibroblasts by full-length N-WASP, by N-WASPΔWA (a mutant unable to activate the Arp2/3 complex), and by N-WASPH208D (a mutant unable to bind Cdc42). IRSp53 failed to induce filopodia in mammalian enabled (Mena)/VASP KO cells, and N-WASP failed to induce filopodia when IRSp53 was knocked down with RNA interference. The IRSp53 I-BAR domain alone induces dynamic membrane protrusions that lack actin and are smaller than normal filopodia (“partial-filopodia”) in both wild-type N-WASP and N-WASP KO cells. We propose that IRSp53 generates filopodia by coupling membrane protrusion through its I-BAR domain with actin dynamics through SH3 domain binding partners, including N-WASP and Mena. Filopodia and lamellipodia are ubiquitous and dynamic actin-based structures at the leading edge of cells that play important roles in processes such as cell invasion, cell migration, phagocytosis, and axonal guidance. Thus, understanding how the formation of filopodia and lamellipodia is regulated will give us insight into the fundamental aspects of cell biology and what goes wrong in disease states such as cancer. Work over the last few years has revealed many of the important players involved in cell signaling events that regulate actin dynamics associated with filopodia and lamellipodia formation (1Higgs H.N. Pollard T. Annu. Rev. Biochem. 2001; 70: 649-676Crossref PubMed Scopus (546) Google Scholar). Rho GTPases (e.g. Cdc42, Rac1, and RhoA) are intimately involved in communication between cell surface receptors and proteins that control actin dynamics (2Jaffe A.B. Hall A. Annu. Rev. Cell Dev. Biol. 2005; 21: 247-269Crossref PubMed Scopus (2377) Google Scholar). Cdc42 is a major regulator of filopodia formation in mammalian cells. The isolation and identification of Cdc42 effectors have opened up the possibility of defining the molecular mechanisms responsible for the regulation and formation of filopodia. To date the Cdc42 effectors N-WASP, 2The abbreviations used are: N-WASP, neuronal Wiskott-Aldrich syndrome protein; BAR, Bin-Amphiphysin-Rsv domain; CRIB, Cdc42/Rac interacting binding region; I-BAR, inverse-Bin-Amphiphysin-Rsv domain; IMD, IRSp53-MIM homology domain; Mena, mammalian enabled; SH3, Src homology domain 3; GFP, green fluorescent protein; KO, knock-out; WT, wild type; RNAi, RNA interference; oligo, oligonucleotides; ROI, region of interest; FRET, fluorescence resonance energy transfer; GST, glutathione S-transferase; FCS, fluorescence correlation spectroscopy; DIC, differential interference contrast; mRFP, monomer red fluorescent protein; KD, knockdown. IRSp53, PAK, and MRCK have been implicated in filopodia formation. In this study we focus on the role of Cdc42 effector IRSp53 and the mechanism by which it induces filopodia formation. The WASP/N-WASP (Wiskott-Aldrich syndrome protein and neuronal-Wiskott-Aldrich syndrome protein) and WAVE1-3 (Wasp family verproline-homologue) family protein complexes are major downstream targets for Rho GTPase (3Stradal T.E. Rottner A. Cell Biol. PubMed Scopus Google Scholar). and proteins are of actin in and proteins of a of as and a binding and the domain and and The domain is involved in binding to the Arp2/3 proteins and interacts directly with of the proteins in the the of this is PubMed Scopus Google A. Rottner T.E. PubMed Scopus Google Scholar). and proteins and A. A. PubMed Scopus Google and binding to N-WASP the protein to the domain to with the Arp2/3 Cell Biol. PubMed Scopus Google PubMed Scopus Google Scholar). the of family proteins are both and is study (3Stradal T.E. Rottner A. Cell Biol. PubMed Scopus Google Scholar). The protein IRSp53 was in a the as T. PubMed Scopus Google Scholar). IRSp53 with and be involved in to proteins T. PubMed Scopus Google and T. Biochem. Scholar). IRSp53 was in a Cdc42 and to be an effector for Cdc42 Cell Biol. 2001; PubMed Scopus Google Hall A. Biol. 2001; PubMed Scopus Google Scholar). IRSp53 consists of an I-BAR the I-BAR the of IRSp53 have protein to the domain 2005; PubMed Scopus Google PubMed Scopus Google Scholar). of the of IRSp53 that it a and has a to the PubMed Scopus Google Scholar). the domain of IRSp53 with a that by A. Cell Biol. PubMed Scopus Google Scholar). we this domain of IRSp53 the domain to as the is an domain in IRSp53 and in and in homology Biochem. PubMed Scopus Google 2005; PubMed Scopus Google a is a for a Cdc42 and interacting binding of the by an an SH3 domain Cell Biol. 2001; PubMed Scopus Google Hall A. 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IRSp53 interacts with the protein through its domain PubMed Scopus Google Scholar). IRSp53 has been to bind the at a the domain Cell Biol. 2005; PubMed Scopus Google Scholar). IRSp53 has and of a actin monomer binding domain at the A. T. A. PubMed Scopus Google T. Biochem. 2001; PubMed Scopus Google Biol. PubMed Scopus Google Scholar). We N-WASP as an of IRSp53-induced filopodia formation. The SH3 domain of IRSp53 can bind N-WASP and IRSp53 to induce filopodia in N-WASP KO fibroblasts Rottner T. 2001; PubMed Scopus Google induce lamellipodia formation and membrane in cells. In N-WASP of N-WASP KO IRSp53 its to induce filopodia formation. the domain the of N-WASP is required to IRSp53 to induce filopodia the domain play a role in filopodia IRSp53 to induce filopodia in KO cells, and N-WASP failed to induce filopodia when IRSp53 was knocked down with The I-BAR domain alone induces dynamic membrane protrusions that lack actin and are smaller than normal filopodia (“partial-filopodia”) in both N-WASP and N-WASP KO cells. We propose that IRSp53 generates filopodia by coupling membrane protrusion through its I-BAR domain with actin dynamics through including N-WASP and via its SH3 cells as in Cell Biol. 2001; PubMed Scopus Google The control and (KO) on cells and with in the of a KO cell of with the been with Rottner T. 2001; PubMed Scopus Google for of and KO cells as Biol. 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Work is to the molecular roles by N-WASP, Mena, and is an SH3 protein with an I-BAR domain of membrane N-WASP is a protein to activate actin via the Arp2/3 is a protein to of actin is protein that can actin in actin dynamics and filopodia formation. We Rottner and for for the N-WASP and KO and and KO cell and and for with

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