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McDaniel AS , Allen JD , Park SJ , Jaffer ZM , Michels EG , Burgin SJ , Chen S , Bessler WK , Hofmann C , Ingram DA , Chernoff J , Clapp DW
Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1(+/-) mast cells
Blood. 2008 Dec;112(12) :4646-4654
PMID: ISI:000261217000042   
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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 Pak1(-/-) 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. (Blood. 2008; 112: 4646-4654)
McDaniel, Andrew S. Allen, Jayme D. Park, Su-Jung Jaffer, Zahara M. Michels, Elizabeth G. Burgin, Sarah J. Chen, Shi Bessler, Waylan K. Hofmann, Clemens Ingram, David A. Chernoff, Jonathan Clapp, D. Wade 51 AMER SOC HEMATOLOGY; 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA 376XT