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Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1.

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.

Pubmed ID: 11266449


  • Keilhack H
  • Müller M
  • Böhmer SA
  • Frank C
  • Weidner KM
  • Birchmeier W
  • Ligensa T
  • Berndt A
  • Kosmehl H
  • Günther B
  • Müller T
  • Birchmeier C
  • Böhmer FD


The Journal of cell biology

Publication Data

January 22, 2001

Associated Grants


Mesh Terms

  • 3T3 Cells
  • Animals
  • Cell Line
  • Epididymis
  • Epithelial Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Mutant Strains
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • Receptor, trkA
  • Recombinant Fusion Proteins
  • Signal Transduction
  • Transfection
  • src Homology Domains