Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/− mast cells
| Autor: | David A. Ingram, Jonathan Chernoff, D. Wade Clapp, Waylan K. Bessler, Andrew S. McDaniel, Clemens Hofmann, Zahara M. Jaffer, Elizabeth G. Michels, Jayme D. Allen, Shi Chen, Su Jung Park, Sarah J. Burgin |
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| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Heterozygote congenital hereditary and neonatal diseases and abnormalities Neurofibromatosis 1 Cellular differentiation Immunology Biology Biochemistry Proto-Oncogene Proteins p21(ras) Mice Genes Neurofibromatosis 1 medicine Animals Mast Cells Cells Cultured Cell Proliferation Mice Knockout Neurofibromin 1 Neoplasia Cell growth Kinase Cell Differentiation Cell Biology Hematology Mast cell nervous system diseases Mice Inbred C57BL Proto-Oncogene Proteins c-kit Phenotype medicine.anatomical_structure p21-Activated Kinases Mitogen-activated protein kinase Cancer research biology.protein Mitogen-Activated Protein Kinases Signal transduction Biomarkers Signal Transduction |
| Zdroj: | Blood. 112:4646-4654 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2008-04-155085 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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