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Protein-tyrosine Phosphatase α Regulates Stem Cell Factor-dependent c-Kit Activation and Migration of Mast Cells*

By Lionel A. Samayawardhena and Catherine J. Pallen


The role of protein-tyrosine phosphatase α (PTPα) in mast cell function was investigated in tissues and cells from PTPα-deficient mice. Bone marrow-derived mast cells (BMMCs) lacking PTPα 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 PTPα-/- 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 PTPα-/- BMMCs. Thus, PTPα 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 PTPα-/- mice

Topics: Mechanisms of Signal Transduction
Publisher: American Society for Biochemistry and Molecular Biology
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Provided by: PubMed Central
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