Journal of Biological Chemistry
Volume 283, Issue 43, 24 October 2008, Pages 29175-29185
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Mechanisms of Signal Transduction
Protein-tyrosine Phosphatase α Regulates Stem Cell Factor-dependent c-Kit Activation and Migration of Mast Cells

https://doi.org/10.1074/jbc.M804077200Get rights and content
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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.

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This work was supported in part by Canadian Institutes of Health Research Grant MOP-49410. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.