Identification of Nck family genes, chromosomal localization, expression, and signaling specificity

Abstract

Already a dozen molecules share binding to the Src homology (SH) 3 domains of human Nck, an SH3-SH3SH3-SH2 adapter protein. We reason that there may be multiple gene members of Nck to accommodate the large binding repertoires. Here we report identification of novel human and mouse Nck genes and rename them as the Nckα and Nckβ genes (including the human Nckα, human Nckβ, mouse Nckα, and mouse Nckβ genes). Nckα and Nckβ share 68% amino acid identity, whereas the two Nckα and two Nckβ across the species show 96% identity to each other. The human Nckβ gene is mapped to 2q12, whereas the human Nckα gene has previously been mapped at 3q21. Antibodies specifically against Nckα and Nckβ detect Nckα and Nckβ with an identical molecular mass in the same cells of various origins. Ectopically expressed Nckβ, but not its SH2 domain mutant, strongly inhibits epidermal growth factor- and platelet-derived growth factor-stimulated DNA synthesis. Consistently, epidermal growth factor receptor and platelet-derived growth factor receptor preferentially interact with Nckβ over Nckα in vitro. This study indicates that Nck is a multiple gene family and that each gene may have its own signaling specificity. Because previous anti-Nck (human Nckα) antibodies cross-react with Nckβ, reassessment of those studies with specific Nck genes would be necessary.