title: Kinase suppressor of Ras (KSR1) modulates multiple kit-ligand-dependent mast cell functions.
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.
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, USA.
authors: Mia
authors: M
authors: Chen
authors: Sarah
authors: S
authors: Burgin
authors: Karl
authors: K
authors: Staser
authors: Yongzheng
authors: Y
authors: He
authors: Xiaohong
authors: X
authors: Li
authors: Mikella
authors: M
authors: Robinson
authors: Li
authors: L
authors: Jiang
authors: Rebecca J
authors: RJ
authors: Chan
authors: David
authors: D
authors: Ingram
authors: D Wade
authors: DW
authors: Clapp
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D003599:Cytoskeleton / Q000378:metabolism / Q000648:ultrastructure; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D007249:Inflammation / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019089:Stem Cell Factor / Q000494:pharmacology*; D054462:p21-Activated Kinases / Q000378:metabolism; D048490:raf Kinases / Q000502:physiology
chemical_list: D019089:Stem Cell Factor; D011494:Protein Kinases; C097199:KSR-1 protein kinase; D054462:p21-Activated Kinases; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases