A new SH2-containing sequence, WC, was isolated by screening cDNA libraries with SH2 representative DNA probes. The WC cDNA is predicted to encode overlapping proteins of 46.6 and 51.7 kd that contain a single C-terminal SH2 domain, and an adjacent glycinelproline-rich motif with regions of homology with the al chain of collagen, but no identifiable catalytic domain. Anti-SHC antibodies recognized three proteins of 46, 52, and 66 kd in a wide range of mammalian cell lines. These SHC proteins complexed with and were phospholylated by activated epidermal growth factor receptor. The physical association of SHC proteins with activated receptbrs was recreated in vitro by using a bacterially expressed SHC SH2 domain. NIH 3T3 mouse fibroblasts that constitutively overexpressed SHC acquired a transformed phenotype in culture and formed tumors in nude mice. These results suggest that the SHC gene products couple activated growth factor receptors to a signallng pathway that regulates the proliferation of mammalian ceils.