Four PSM/SH2-B alternative splice variants and their differential roles inmitogenesis

An SH2 domain originally termed SH2-B had been identified as a direct cellu lar binding target of a number of mostly mitogenic receptors. The complete cellular protein, termed PSM, and respective sequence variants share additi onal Pro-rich and PH regions, as well as similarities with APS and Lnk. A r ole of these mediators has been implicated in signaling pathways found down stream of growth hormone receptor and receptor tyrosine kinases, including the insulin, insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), nerve growth factor, hepatocyte growth factor, and fibroblas t growth factor receptors. As a result of this report a total of four PSM/S H2-B sequence variants termed alpha, beta, gamma, and delta have now been i dentified in the mouse and have been compared with the available rat and hu man sequences. Variant differences are based on alternative splicing and de fine distinct last exons 7, 8, and 9 that result in reading frameshifts and unique carboxyl-terminal amino acid sequences. Variant sequences have been identified from cDNA libraries and directly by reverse transcription-polym erase chain reaction. Sequence analysis predicts four distinctly sized prot ein products that have been demonstrated after cDNA expression. All were fo und phosphorylated on tyrosine specifically in response to IGF-I and PDGF s timulation. cDNA expression of the four variants caused variant-dependent l evels of stimulation of IGF-I- and PDGF-induced mitogenesis. The most prono unced increase in mitogenesis was consistently observed for the delta varia nt followed by delta, alpha, and beta with decreasing responses. In contras t, the mitogenic response to epidermal growth factor consistently remained unaffected. The variants are expressed in most mouse tissues, typically, mo st strongly in pairs of alpha and delta or beta and gamma. Our findings imp licate differential roles of the PSM/SH2-B splice variants in specific mito genic signaling pathways.