| First Author | McDaniel AS | Year | 2008 |
| Journal | Blood | Volume | 112 |
| Issue | 12 | Pages | 4646-54 |
| PubMed ID | 18768391 | Mgi Jnum | J:142439 |
| Mgi Id | MGI:3821520 | Doi | 10.1182/blood-2008-04-155085 |
| Citation | McDaniel AS, et al. (2008) Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/- mast cells. Blood 112(12):4646-54 |
| abstractText | 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. |
