Negative Regulation of Ros Receptor Tyrosine Kinase Signaling

• Published in: The Journal of cell biology 2001-01, Vol.152 (2), p.325-334
• Main Authors: Keilhack, Heike, Müller, Marit, Böhmer, Sylvia-Annette, Frank, Carsten, Weidner, K. Michael, Birchmeier, Walter, Ligensa, Tanja, Berndt, Alexander, Kosmehl, Hartwig, Günther, Bernd, Müller, Thomas, Birchmeier, Carmen, Böhmer, Frank D.
• Format: Article
• Language: English
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.152.2.325

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.