Mammalian Nck1 and Nck2 are closely related adaptor proteins that possess three SH3 domains, followed by an SH2 domain, and are implicated in coupling phosphotyrosine signals to polypeptides that regulate the actin cytoskeleton. However, the in vivo functions of Nck1 and Nck2 have not been defined. We have mutated the murine Nck1 and Nck2 genes and incorporated -galactosidase reporters into the mutant loci. In mouse embryos, the two Nck genes have broad and overlapping expression patterns. They are functionally redundant in the sense that mice deficient for either Nck1 or Nck2 are viable, whereas inactivation of both Nck1 and Nck2 results in profound defects in mesoderm-derived notochord and embryonic lethality at embryonic day 9.5.
Fibroblast cell lines derived from Nck1؊/؊ Nck2 ؊/؊ embryos have defects in cell motility and in the organization of the lamellipodial actin network. These data suggest that the Nck SH2/SH3 adaptors have important functions in the development of mesodermal structures during embryogenesis, potentially linked to a role in cell movement and cytoskeletal organization.Signaling by cell surface receptors commonly involves the recruitment of cytoplasmic targets into multiprotein complexes through specialized interaction domains. These domains provide a mechanism to couple different receptors to the core machinery that regulates cellular function and to provide a degree of specificity in signal transduction. Receptors with intrinsic or associated tyrosine kinase activity commonly recruit their targets through phosphotyrosine-containing motifs that bind the Src homology 2 (SH2) domains of cytoplasmic regulatory proteins (30,45). Although some of these SH2-containing polypeptides have linked catalytic domains, others have an adaptor function and are comprised exclusively of interaction domains that nucleate the assembly of protein complexes around the activated receptor. Adaptors of the Nck, Grb2, and Crk families contain a single SH2 domain and various numbers of SH3 domains that typically bind to effector proteins through proline-rich peptide motifs. Each of these adaptors preferentially binds a distinct phosphotyrosine-containing motif through its SH2 domain and a specific group of signaling proteins through its SH3 domains. Grb2, for example, links phosphorylated Tyr-X-Asn sequences on activated receptor tyrosine kinases (RTKs) to proteins such as Sos and Gab1, involved in Ras/mitogen-activated protein (MAP) kinase and phosphatidylinositol 3Ј-kinase signaling (34,36,48).Nck adaptor proteins possess three SH3 domains, followed by a C-terminal SH2 domain that binds optimally to pYDEP/
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