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 Ingram, Jonathan Chernoff, D. Clapp

Research output: Contribution to journalArticle

58 Citations (Scopus)

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

Fingerprint

p21-Activated Kinases
Mast Cells
Neurofibromatosis 1
Phenotype
Neurofibromin 1
Neurofibroma
Inborn Genetic Diseases
Cell growth
Modulators
Tumors
Skin
Mutation
Growth

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

McDaniel, A. S., Allen, J. D., Park, S. J., Jaffer, Z. M., Michels, E. G., Burgin, S. J., ... Clapp, D. (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

Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/ mast cells. / 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; Chernoff, Jonathan; Clapp, D.

In: Blood, Vol. 112, No. 12, 01.12.2008, p. 4646-4654.

Research output: Contribution to journalArticle

McDaniel, AS, Allen, JD, Park, SJ, Jaffer, ZM, Michels, EG, Burgin, SJ, Chen, S, Bessler, WK, Hofmann, C, Ingram, D, Chernoff, J & Clapp, D 2008, 'Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/ mast cells', Blood, vol. 112, no. 12, pp. 4646-4654. https://doi.org/10.1182/blood-2008-04-155085
McDaniel AS, Allen JD, Park SJ, Jaffer ZM, Michels EG, Burgin SJ et al. Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/ mast cells. Blood. 2008 Dec 1;112(12):4646-4654. https://doi.org/10.1182/blood-2008-04-155085
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 ; Chernoff, Jonathan ; Clapp, D. / Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/ mast cells. In: Blood. 2008 ; Vol. 112, No. 12. pp. 4646-4654.
@article{ff27cefd99d9420ba65c23cc331d2850,
title = "Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/ mast cells",
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.",
author = "McDaniel, {Andrew S.} and Allen, {Jayme D.} and Park, {Su Jung} and Jaffer, {Zahara M.} and Michels, {Elizabeth G.} and Burgin, {Sarah J.} and Shi Chen and Bessler, {Waylan K.} and Clemens Hofmann and David Ingram and Jonathan Chernoff and D. Clapp",
year = "2008",
month = "12",
day = "1",
doi = "10.1182/blood-2008-04-155085",
language = "English",
volume = "112",
pages = "4646--4654",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "12",

}

TY - JOUR

T1 - Pak1 regulates multiple c-Kit mediated Ras-MAPK gain-in-function phenotypes in Nf1+/ mast cells

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

AU - Chernoff, Jonathan

AU - Clapp, D.

PY - 2008/12/1

Y1 - 2008/12/1

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 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=58149401317&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149401317&partnerID=8YFLogxK

U2 - 10.1182/blood-2008-04-155085

DO - 10.1182/blood-2008-04-155085

M3 - Article

VL - 112

SP - 4646

EP - 4654

JO - Blood

JF - Blood

SN - 0006-4971

IS - 12

ER -