Abstract

Keywords

PSM, a mediator of PDGF-BB-, IGF-I-, and insulin-stimulated mitogenesis

Heimo Riedel^1,2, Nasim Yousaf¹, Yuyuan Zhao⁴, Dai Heping^1,3, Youping Deng¹ & Jian Wang¹

Correspondence to: Heimo Riedel, Department of Biological Sciences, 2171 BSB, Wayne State University, Detroit, Michigan MI 48202-3917, USA

³Current address: Institute of Hydrobiology, Chinese Acadamy of Sciences, Wuhan, 430072, China

⁴Deceased

PSM/SH2-B has been described as a cellular partner of the FcRI receptor, insulin receptor (IR), insulin-like growth factor-I (IGF-I) receptor (IGF-IR), and nerve growth factor receptor (TrkA). A function has been proposed in neuronal differentiation and development but its role in other signaling pathways is still unclear. To further elucidate the physiologic role of PSM we have identified additional mitogenic receptor tyrosine kinases as putative PSM partners including platelet-derived growth factor (PDGF) receptor (PDGFR) beta, hepatocyte growth factor receptor (Met), and fibroblast growth factor receptor. We have mapped Y740 as a site of PDGFR beta that is involved in the association with PSM. We have further investigated the putative role of PSM in mitogenesis with three independent experimental strategies and found that all consistently suggested a role as a positive, stimulatory signaling adapter in normal NIH3T3 and baby hamster kidney fibroblasts. (1) PSM expression from cDNA using an ecdysone-regulated transient expression system stimulated PDGF-BB-, IGF-I-, and insulin- but not EGF-induced DNA synthesis in an ecdysone dose-responsive fashion; (2) Microinjection of the (dominant negative) PSM SH2 domain interfered with PDGF-BB- and insulin-induced DNA synthesis; and (3) A peptide mimetic of the PSM Pro-rich putative SH3 domain-binding region interfered with PDGF-BB-, IGF-I-, and insulin- but not with EGF-induced DNA synthesis in NIH3T3 fibroblasts. This experiment was based on cell-permeable fusion peptides with the Drosophila antennapedia homeodomain which effectively traverse the plasma membrane of cultured cells. These experimental strategies independently suggest that PSM functions as a positive, stimulatory, mitogenic signaling mediator in PDGF-BB, IGF-I, and insulin but not in EGF action. This function appears to involve the PSM SH2 domain as well as the Pro-rich putative SH3 domain binding region. Our findings support the model that PSM participates as an adapter in various mitogenic signaling mechanisms by linking an activated (receptor) phospho-tyrosine to the SH3 domain of an unknown cellular partner. Oncogene (2000) 19, 39 – 50.

^© Macmillan Publishers Ltd 2000