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

H Keilhack; M Müller; S A Böhmer; C Frank; K M Weidner; W Birchmeier; T Ligensa; A Berndt; H Kosmehl; B Günther; T Müller; C Birchmeier; F D Böhmer

doi:10.1083/jcb.152.2.325

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

J Cell Biol. 2001 Jan 22;152(2):325-34. doi: 10.1083/jcb.152.2.325.

Authors

H Keilhack¹, M Müller, S A Böhmer, C Frank, K M Weidner, W Birchmeier, T Ligensa, A Berndt, H Kosmehl, B Günther, T Müller, C Birchmeier, F D Böhmer

Affiliation

¹ Research Unit, Molecular Cell Biology, D-07747 Jena, Germany.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Intracellular Signaling Peptides and Proteins
Proto-Oncogene Proteins
Recombinant Fusion Proteins
Protein-Tyrosine Kinases
ROS1 protein, human
Receptor Protein-Tyrosine Kinases
Receptor, trkA
Ros1 protein, mouse
PTPN6 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Protein Tyrosine Phosphatases
Ptpn6 protein, mouse