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

Oncogene volume 19, pages 39–50 (2000)Cite this article

Abstract

PSM/SH2-B has been described as a cellular partner of the FcεRI 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.

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Acknowledgements

We thank in particular Benjamin R Braun, and Dr O Rama Swamy, Michelle E Leone, Amale Boufelliga, Rukmani Krishnamoorthy, Jeffrey Vang, Christina Roffi, Veronica Kemerko, Isam Abbarrah, Wissam Malouf, and Dr Youhou Kang for technical help. We are grateful to Drs Janne Balsamo, Jonathan Cooper, Robert E Friesel, Barbara L Hempstead, Jerrold M Olefsky, Moraq Park, Tony Pawson, Avraham Raz and Morris F White for cell lines, plasmids, or expressed proteins, Gert Wolf and Zhou Songyang for support, and Nora Riedel for ideas and the critical discussion of the manuscript. Part of this work was supported (to H Riedel) by the National Science Foundation under Grant No. MCB-9316997 and MCB-9696090, by the Juvenile Diabetes Foundation International under Grant No. 197048, by the National Institutes of Health under Grant R01 CA77873 and by the Barbara Ann Karmanos Cancer Institute with a Virtual Discovery Grant.

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  1. Dai Heping

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

  2. Yuyuan Zhao: Deceased

Authors and Affiliations

  1. Department of Biological Sciences, Wayne State University, Detroit, 48202, Michigan, MI, USA

    Heimo Riedel, Nasim Yousaf, Dai Heping, Youping Deng & Jian Wang

  2. Member, Barbara Ann Karmanos Cancer Institute, Detroit, 48201, Michigan, MI, USA

    Heimo Riedel

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Riedel, H., Yousaf, N., Zhao, Y. et al. PSM, a mediator of PDGF-BB-, IGF-I-, and insulin-stimulated mitogenesis. Oncogene 19, 39–50 (2000). https://doi.org/10.1038/sj.onc.1203253

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