Submitted April 30, 2008
Accepted July 26, 2008
Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/- mast cells
Andrew S. McDaniel, Jayme D Allen, Su-Jung Park, Zahara M Jaffer, Elizabeth G Michels, Sarah J Burgin, Shi Chen, Waylan K Bessler, Clemens Hofmann, David A Ingram, Jonathan Chernoff, and D Wade Clapp*
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States
Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
Fox Chase Cancer Center, Philadelphia, PA, United States
* Corresponding author; email: dclapp{at}iupui.edu.
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. Utilizing an intercross of Pak 1-/- mice with Nf1+/- mice, we determined that Pak1 regulates hyperactive Ras-dependent proliferation via a Pak1/Erk pathway, while a Pak1/p38 pathway is required for the increased migration in Nf1+/- mast cells. Further, 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.
