Kinase suppressor of ras (ksr1) modulates multiple kit-ligand-dependent mast cell functions

Mia Chen, Sarah Burgin, Karl Staser, Yongzheng He, Xiaohong Li, Mikella Robinson, Li Jiang, Rebecca Chan, David Ingram, D. Clapp

Research output: Contribution to journalArticle

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Abstract

The intricately regulated Ras pathway coordinates multiple kit-ligand-induced mast cell functions, including chemotaxis, proliferation, and degranulation. However, the intracellular proteins that modulate the intensity and duration of stem cell factor-induced signals and the consequent cellular response are incompletely understood. Scaffolding proteins coordinate the spatial organization of mitogen-activated protein kinase proteins that may potentiate and/or inhibit cell functions. The kinase suppressor of Ras (KSR1) protein is known to function as a molecular scaffold and coordinates the organization of Raf/Mek/Erk in response to receptor tyrosine kinases. However, the impact of KSR1 in myeloid mast cell functions and in response to stem cell factor remains unknown. In the present study, we investigated the role of KSR1 in regulating cellular functions of bone marrow-derived mast cells of KSR1-deficient ( -/-) mice. Genetic disruption of KSR1 resulted in both striking reductions in kit-ligand-mediated proliferation and degranulation, which are commonly attributed to mitogen-activated protein kinase signals. Surprisingly, disruption of the KSR1 scaffold also resulted in a decline in migration that is generally not linked to Raf-Erk signals. We found that loss of KSR1 does impact the biochemical activation of p21-activated kinase, a kinase that is known to modulate Raf-Erk signals and also F-actin polymerization key to mast cell migration. Collectively, these studies demonstrate that the scaffolding protein KSR1 has an important role in multiple kit-ligand-mediated mast cell functions. This study elucidates varied mast cell physiological functions for KSR1, including those related to cytoskeletal organization, and it suggests a novel molecular target for attenuating mast cell-mediated inflammation.

Original languageEnglish
Pages (from-to)969-976
Number of pages8
JournalExperimental Hematology
Volume39
Issue number10
DOIs
StatePublished - Oct 2011

Fingerprint

Stem Cell Factor
Mast Cells
Mitogen-Activated Protein Kinases
Proteins
p21-Activated Kinases
ras Proteins
Receptor Protein-Tyrosine Kinases
Chemotaxis
Myeloid Cells
KSR-1 protein kinase
Polymerization
Cell Movement
Actins
Phosphotransferases
Bone Marrow
Inflammation

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Molecular Biology
  • Hematology

Cite this

Kinase suppressor of ras (ksr1) modulates multiple kit-ligand-dependent mast cell functions. / Chen, Mia; Burgin, Sarah; Staser, Karl; He, Yongzheng; Li, Xiaohong; Robinson, Mikella; Jiang, Li; Chan, Rebecca; Ingram, David; Clapp, D.

In: Experimental Hematology, Vol. 39, No. 10, 10.2011, p. 969-976.

Research output: Contribution to journalArticle

Chen, Mia ; Burgin, Sarah ; Staser, Karl ; He, Yongzheng ; Li, Xiaohong ; Robinson, Mikella ; Jiang, Li ; Chan, Rebecca ; Ingram, David ; Clapp, D. / Kinase suppressor of ras (ksr1) modulates multiple kit-ligand-dependent mast cell functions. In: Experimental Hematology. 2011 ; Vol. 39, No. 10. pp. 969-976.
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