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

作者：Samayawardhena Lionel A; Pallen Catherine J^*

来源：Journal of Biological Chemistry, 2008, 283(43): 29175-29185.

DOI：10.1074/jbc.M804077200

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

• 出版日期2008-10-24