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

@article{citeulike:3197930, 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 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.}, address = {Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States.}, author = {McDaniel, Andrew S S. and Allen, Jayme D D. and Park, Su-Jung J. and Jaffer, Zahara M M. and Michels, Elizabeth G G. and Burgin, Sarah J J. and Chen, Shi and Bessler, Waylan K K. and Hofmann, Clemens and Ingram, David A A. and Chernoff, Jonathan and Clapp, D Wade W. }, citeulike-article-id = {3197930}, doi = {http://dx.doi.org/10.1182/blood-2008-04-155085}, issn = {1528-0020}, journal = {Blood}, keywords = {cell, mast, nf1, pak1, ras}, month = {September}, posted-at = {2008-09-05 19:21:03}, priority = {4}, title = {Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/- mast cells.}, url = {http://dx.doi.org/10.1182/blood-2008-04-155085}, year = {2008} }

TY - JOUR ID - citeulike:3197930 L3 - citeulike-article-id:3197930 N2 - 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. JF - Blood SN - 1528-0020 AD - Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States. TI - Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/- mast cells. KW - cell KW - mast KW - nf1 KW - pak1 KW - ras AU - McDaniel, Andrew S AU - Allen, Jayme D AU - Park, Su-Jung AU - Jaffer, Zahara M AU - Michels, Elizabeth G AU - Burgin, Sarah J AU - Chen, Shi AU - Bessler, Waylan K AU - Hofmann, Clemens AU - Ingram, David A AU - Chernoff, Jonathan AU - Clapp, D Wade PY - 2008/09/02/ UR - http://dx.doi.org/10.1182/blood-2008-04-155085 ER -