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c-Src association with and phosphorylation of p58gag, a membrane- and microfilament-associated retroviral Gag-like protein in a xenotransplantable rat mammary tumor

Oncogene volume 18, pages 4099–4107 (1999)Cite this article

Abstract

The retroviral Gag-like protein p58gag expressed in a highly metastatic ascites rat mammary adenocarcinoma has been implicated in cell surface changes contributing to xenotransplantability. p58gag is present in the cells in a plasma membrane- and microfilament-associated signal transduction particle containing Src and is phosphorylated on tyrosine. Overlay analyses and affinity chromatography with glutathione S-transferase (GST) fusion proteins of Src homology-3 (SH3) domains showed direct binding of the Src but not the Crk SH3 domain to p58gag. This association was confirmed by co-immunoprecipitation of partially purified p58gag from ascites cell lysates with platelet Src. Further, a GST-p58gag fusion protein bound full length c-Src from either platelets or c-Src-expressing insect cells. The GST-p58gag fusion protein, but not GST, was phosphorylated by platelet or insect cell-expressed c-Src, but not by a kinase negative c-Src variant. The binding of GST-p58gag to c-Src was almost completely abolished by a 50-fold excess of the GST-SH3 domain of Src, and a parallel decrease in tyrosine phosphorylation of p58gag was observed. These results demonstrate that p58gag is tyrosine-phosphorylated as a consequence of its specific association with c-Src via its SH3 domain. These observations suggest a mechanism by which Gag proteins may contribute to retroviral maturation or pathogenesis through binding and relocalization of SH3 domain-containing proteins such as Src-like tyrosine kinases to sites of association of microfilaments with the plasma membrane.

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Acknowledgements

We would like to thank Dr Kermit L Carraway III (Beth Israel Hospital, Harvard, USA) for kindly providing Src kinase-negative mutant reagents. We are indebted to Drs Rick Van Etten (Brigham and Women's Hospital, Harvard, USA) and Nevis Fregien (University of Miami) for valuable advice and discussions. This work was supported in part by grants from the National Institutes of Health (CA72577-01A1) and the Sylvester Comprehensive Cancer Center of the University of Miami (National Institutes of Health Grant CA 14395) and a predoctoral fellowship to Jiaqi Huang from the American Heart Association, Florida Division.

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Authors and Affiliations

  1. Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL 33101, Florida, USA

    Jiaqi Huang, Bao-Tong Zhang, Yongqing Li & Coralie A Carothers Carraway

  2. Cell Biology & Anatomy, University of Miami School of Medicine, Miami, Florida, 33101, FL, USA

    Kermit L Carraway

  3. Howard Hughes Institute, Children's Hospital, Harvard, Boston, MA 02115, Massachusetts, USA

    Bruce Mayer

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Huang, J., Zhang, BT., Li, Y. et al. c-Src association with and phosphorylation of p58gag, a membrane- and microfilament-associated retroviral Gag-like protein in a xenotransplantable rat mammary tumor. Oncogene 18, 4099–4107 (1999). https://doi.org/10.1038/sj.onc.1202779

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