Protein-tyrosine phosphatase alpha regulates stem cell factor-dependent c-Kit activation and migration of mast cells.
The role of protein-tyrosine phosphatase alpha (PTPalpha) in mast cell function was investigated in tissues and cells from PTPalpha-deficient mice. Bone marrow-derived mast cells (BMMCs) lacking PTPalpha exhibit defective stem cell factor (SCF)-dependent polarization and migration. Investigation of the molecular basis for this reveals that SCF/c-Kit-stimulated activation of the Fyn tyrosine kinase is impaired in PTPalpha(-/-) BMMCs, with a consequent inhibition of site-specific c-Kit phosphorylation at tyrosines 567/569 and 719. Although c-Kit-mediated activation of phosphatidylinositol 3-kinase and Akt is unaffected, profound defects occur in the activation of downstream signaling proteins, including mitogen-activated protein kinases and Rho GTPases. Phosphorylation and interaction of Fyn effectors Gab2 and Shp2, which are linked to Rac/JNK activation in mast cells, are impaired in PTPalpha(-/-) BMMCs. Thus, PTPalpha is required for SCF-induced c-Kit and Fyn activation, and in this way regulates a Fyn-based c-Kit signaling axis (Fyn/Gab2/Shp2/Vav/PAK/Rac/JNK) that mediates mast cell migration. These defective signaling events may underlie the altered tissue-resident mast cell populations found in PTPalpha(-/-) mice.
Samayawardhena
Lionel A
LA
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
Pallen
Catherine J
CJ
D000818:Animals; D002465:Cell Movement; D003433:Crosses, Genetic; D015971:Gene Expression Regulation, Enzymologic; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000502:physiology*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D019089:Stem Cell Factor; D019869:Phosphatidylinositol 3-Kinases; D019009:Proto-Oncogene Proteins c-kit; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D020764:cdc42 GTP-Binding Protein