Negative regulation of Ros receptor tyrosine kinase signaling: An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1
Authors
- H. Keilhack
- M. Mueller
- S.A. Boehmer
- C. Frank
- K.M. Weidner
- W. Birchmeier
- T. Ligensa
- A. Berndt
- H. Kosmehl
- B. Gunther
- T. Mueller
- C. Birchmeier
- F.D. Boehmer
Journal
- Journal of Cell Biology
Citation
- J Cell Biol 152 (2): 325-334
Abstract
Male "viable motheaten" (me(v)) 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 me(v) 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 NH(2)-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.