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© The Rockefeller University Press,
0021-9525/2001//325 $5.00
The Journal of Cell Biology, Volume 152, Number 2,
, 2001 325-334
Original Article |
Negative Regulation of Ros Receptor Tyrosine Kinase Signaling
: An Epithelial Function of the Sh2 Domain Protein Tyrosine Phosphatase Shp-1
b Institute of Pathology, D-07747 Jena, Germany
c Institute of Experimental Animal Investigation Friedrich-Schiller-Universität, D-07747 Jena, Germany
d Max-Delbrück-Centrum für Molekulare Medizin, Department of Cell Biology, 13122 Berlin, Germany
e Max-Delbrück-Centrum für Molekulare Medizin, Department of Medical Genetics, 13122 Berlin, Germany
f Roche-Pharma Research, D-82377 Penzberg, Germany
Research Unit, Molecular Cell Biology, Drackendorfer Strasse 1, D-07747 Jena, Germany.49-36-41-30-44-6249-36-41-30-44-60
i5frbo{at}rz.uni-jena.de
Male "viable motheaten" (mev) mice, with a naturally occurring mutation in the gene of the SH2 domain protein tyrosine phosphatase SHP-1, are sterile. Known defects in sperm maturation in these mice correlate with an impaired differentiation of the epididymis, which has similarities to the phenotype of mice with a targeted inactivation of the Ros receptor tyrosine kinase. Ros and SHP-1 are coexpressed in epididymal epithelium, and elevated phosphorylation of Ros in the epididymis of mev mice suggests that Ros signaling is under control of SHP-1 in vivo. Phosphorylated Ros strongly and directly associates with SHP-1 in yeast two-hybrid, glutathione S-transferase pull-down, and coimmunoprecipitation experiments. Strong binding of SHP-1 to Ros is selective compared to six other receptor tyrosine kinases. The interaction is mediated by the SHP-1 NH2-terminal SH2 domain and Ros phosphotyrosine 2267. Overexpression of SHP-1 results in Ros dephosphorylation and effectively downregulates Ros-dependent proliferation and transformation. We propose that SHP-1 is an important downstream regulator of Ros signaling.
Key Words: protein tyrosine phosphatase • regulation • receptor tyrosine kinase • epididymis • fertility
© 2001 The Rockefeller University Press
Abbreviations used in this paper: aa, amino acid; ATc, anhydrotetracycline; Erk, extracellular signal regulated kinase; GST, glutathione S-transferase; me, motheaten; mev, viable motheaten; NGF, nerve growth factor; PDGF, platelet-derived growth factor; PTP, protein tyrosine phosphatase; RTK, receptor tyrosine kinase.
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