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PMID:11266449

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Citation

Keilhack, H, Müller, M, Böhmer, SA, Frank, C, Weidner, KM, Birchmeier, W, Ligensa, T, Berndt, A, Kosmehl, H, Günther, B, Müller, T, Birchmeier, C and Böhmer, FD (2001) Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of the SH2 domain protein tyrosine phosphatase SHP-1. J. Cell Biol. 152:325-34

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.

Links

PubMed PMC2199605

Keywords

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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PTN6

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q78DX7

F

Seeded From UniProt

complete

HUMAN:PTN6

involved_in

GO:0030154: cell differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTN6

enables

GO:0005001: transmembrane receptor protein tyrosine phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PTN6

involved_in

GO:0006470: protein dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PTN6

involved_in

GO:0070372: regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PTN6

involved_in

GO:1905867: epididymis development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ROS1

enables

GO:0019903: protein phosphatase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P29350

F

Seeded From UniProt

complete

MOUSE:ROS1

involved_in

GO:0030154: cell differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ROS1

involved_in

GO:0006468: protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ROS1

involved_in

GO:0070372: regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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