Abstract
An SH2 domain originally termed SH2-B had been identified as a direct cellular binding target of a number of mostly mitogenic receptors. The complete cellular protein, termed PSM, and respective sequence variants share additional Pro-rich and PH regions, as well as similarities with APS and Lnk. A role of these mediators has been implicated in signaling pathways found downstream 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 fibroblast growth factor receptors. As a result of this report a total of four PSM/SH2-B sequence variants termed alpha, beta, gamma, and delta have now been identified in the mouse and have been compared with the available rat and human sequences. Variant differences are based on alternative splicing and define 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-polymerase chain reaction. Sequence analysis predicts four distinctly sized protein products that have been demonstrated after cDNA expression. All were found phosphorylated on tyrosine specifically in response to IGF-I and PDGF stimulation. cDNA expression of the four variants caused variant-dependent levels of stimulation of IGF-I- and PDGF-induced mitogenesis. The most pronounced increase in mitogenesis was consistently observed for the gamma variant followed by delta, alpha, and beta with decreasing responses. In contrast, the mitogenic response to epidermal growth factor consistently remained unaffected. The variants are expressed in most mouse tissues, typically, most strongly in pairs of alpha and delta or beta and gamma. Our findings implicate differential roles of the PSM/SH2-B splice variants in specific mitogenic signaling pathways.
Highlights
PSM has been identified as a mouse protein based on its association with the activated catalytic insulin receptor (IR)1 domain in a yeast two-hybrid screen [1, 2]
An association of PSM/src homology 2 (SH2)-B was established with the insulin-like growth factor-I (IGF-I) receptor (IGF-IR) that depends on receptor activation and was mapped to phospho-tyrosine sites that are conserved between the insulin and IGF-I receptors [8]
An association with platelet-derived growth factor receptor (PDGFR) in response to PDGF activation was described for PSM/SH2-B that stimulated its phosphorylation on tyrosine, serine, and threonine [9, 10]
Summary
PSM has been identified as a mouse protein based on its association with the activated catalytic insulin receptor (IR) domain in a yeast two-hybrid screen [1, 2]. A variant form of PSM/SH2-B, termed beta, has been reported which carries an additional 100 bp of coding region downstream of the SH2 domain and is predicted to result in a shortened protein product [2, 4]. This variant was described as a substrate and as a potent cytoplasmic activator of the tyrosine kinase JAK2 in response to growth hormone signaling [4,5,6]. A single gene has been mapped to the distal arm of mouse chromosome 7 in a region linked to obesity in mice [13]
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