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, D. Wade Clapp

Research output: Contribution to journalArticle

61 Scopus citations

Abstract

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 cytoskel-etal 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.

Original languageEnglish (US)
Pages (from-to)4646-4654
Number of pages9
JournalBlood
Volume112
Issue number12
DOIs
StatePublished - Dec 1 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/ mast cells'. Together they form a unique fingerprint.

  • Cite this

    McDaniel, A. S., Allen, J. D., Park, S. J., Jaffer, Z. M., Michels, E. G., Burgin, S. J., Chen, S., Bessler, W. K., Hofmann, C., Ingram, D. A., Chernoff, J., & Clapp, D. W. (2008). Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/ mast cells. Blood, 112(12), 4646-4654. https://doi.org/10.1182/blood-2008-04-155085