Protein-tyrosine phosphatase alpha regulates stem cell factor-dependent c-Kit activation and migration of mast cells.

The Journal of Biological Chemistry
Lionel A Samayawardhena, Catherine J Pallen

Abstract

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.

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Citations

Feb 3, 2011·Cancer Metastasis Reviews·Khashayarsha KhazaieDavid J Bentrem
Dec 2, 2010·Molecular Biology of the Cell·Maria Teresa Herrera AbreuRoger J Daly
May 6, 2015·European Journal of Pharmacology·Petr DraberToshiaki Kawakami
Dec 3, 2008·Cell Calcium·Takahiro ShimizuRudi Vennekens
Oct 18, 2012·Physiological Reviews·Johan Lennartsson, Lars Rönnstrand
Dec 17, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Madeleine RådingerAlasdair M Gilfillan
Oct 15, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Lionel A Samayawardhena, Catherine J Pallen
Apr 16, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Namit SharmaAndrew W B Craig

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