title: Requirement of Nck adaptors for actin dynamics and cell migration stimulated by platelet-derived growth factor B.
abstract: The Nck family of Src homology (SH) 2/SH3 domain adaptors functions to link tyrosine phosphorylation induced by extracellular signals with downstream regulators of actin dynamics. We investigated the role of mammalian Nck adaptors in signaling from the activated platelet-derived growth factor (PDGF) receptor (PDGFbetaR) to the actin cytoskeleton. We report here that Nck adaptors are required for cytoskeletal reorganization and chemotaxis stimulated by PDGF-B. Analysis of tyrosine-phosphorylated proteins demonstrated that Crk-associated substrate (p130(Cas)), not the activated PDGFbetaR itself, is the major Nck SH2 domain-binding protein in PDGF-B-stimulated cells. Both Nck- and p130(Cas)-deficient cells fail to display cytoskeletal rearrangements, including the formation of membrane ruffles and the disassembly of actin bundles, typically shown by their WT counterparts in response to PDGF-B. Furthermore, Nck and p130(Cas) colocalize in phosphotyrosine-enriched membrane ruffles induced by PDGF-B in NIH 3T3 cells. These results suggest that Nck adaptors play an essential role in linking the activated PDGFbetaR with actin dynamics through a pathway that involves p130(Cas).
authors.affiliation: Raymond and Beverly Sackler Laboratory of Genetics and Molecular Medicine, Department of Genetics and Developmental Biology and Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Rivera
authors.forename: S
authors.initials: S
authors.lastname: Antoku
authors.forename: S
authors.initials: S
authors.lastname: Gelkop
authors.forename: N Y
authors.initials: NY
authors.lastname: Shin
authors.forename: S K
authors.initials: SK
authors.lastname: Hanks
authors.forename: T
authors.initials: T
authors.lastname: Pawson
authors.forename: B J
authors.initials: BJ
authors.lastname: Mayer
mesh_terms: D000199:Actins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D050719:Crk-Associated Substrate Protein; C078332:Nck protein; C117758:Nck2 protein, mouse; D015513:Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D019000:Phosphotyrosine; D020797:Receptor, Platelet-Derived Growth Factor beta