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 Blood, 1 December 2008, Vol. 112, No. 12, pp. 4646-4654.
Prepublished online as a Blood First Edition Paper on September 2, 2008; DOI 10.1182/blood-2008-04-155085.

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NEOPLASIA

Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/– mast cells

Andrew S. McDaniel1,2, Jayme D. Allen2,3, Su-Jung Park2,3, Zahara M Jaffer4, Elizabeth G. Michels2,3, Sarah J. Burgin2,3, Shi Chen2,3, Waylan K. Bessler2,3, Clemens Hofmann4, David A. Ingram2,3, Jonathan Chernoff4, and D. Wade Clapp13

1 Department of Microbiology and Immunology, 2 Herman B Wells Center for Pediatric Research, and 3 Department of Pediatrics, Indiana University School of Medicine, Indianapolis; and 4 Fox Chase Cancer Center, Philadelphia, PA

Neurofibromatosis type 1 (NF1) is a common genetic disorder caused by mutations in the NF1 locus, which encodes neurofibromin, a negative regulator of Ras. Patients with NF1 develop numerous neurofibromas, which contain many inflammatory mast cells that contribute to tumor formation. Subsequent to c-Kit stimulation, signaling from Ras to Rac1/2 to the MAPK pathway appears to be responsible for multiple hyperactive mast cell phenotypes; however, the specific effectors that mediate these functions remain uncertain. p21-activated kinase 1 (Pak1) is a downstream mediator of Rac1/2 that has been implicated as a positive regulator of MAPK pathway members and is a modulator of cell growth and cytoskeletal dynamics. Using an intercross of Pak 1–/– mice with Nf1+/– mice, we determined that Pak1 regulates hyperactive Ras-dependent proliferation via a Pak1/Erk pathway, whereas a Pak1/p38 pathway is required for the increased migration in Nf1+/– mast cells. Furthermore, we confirmed that loss of Pak1 corrects the dermal accumulation of Nf1+/– mast cells in vivo to levels found in wild-type mice. Thus, Pak1 is a novel mast cell mediator that functions as a key node in the MAPK signaling network and potential therapeutic target in NF1 patients.


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