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J. Biol. Chem., Vol. 283, Issue 43, 29175-29185, October 24, 2008

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

Lionel A. Samayawardhena and Catherine J. Pallen, Recipient of an investigator award from the Child and Family Research Institute^¶1

From the Departments of Pediatrics and ^¶Pathology and Laboratory Medicine and the Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada

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

Received for publication, May 28, 2008 , and in revised form, August 7, 2008.

^* 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.

¹ To whom correspondence should be addressed: 3102-950 West 28th Ave., Vancouver, BC V5Z 4H4, Canada. Tel.: 604-875-2439; Fax: 604-875-2417; E-mail: cpallen{at}interchange.ubc.ca.

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