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Raf-1 is a serine/threonine protein kinase that has an essential role in cell proliferation. The mechanisms that regulate Raf-1 in airway smooth muscle are not well understood. In this study, treatment with platelet-derived growth factor (PDGF) induced spatial redistribution of Raf-1 from the cytoplasm to the periphery of human airway smooth muscle cells. Moreover, a pool of Raf-1 was found in F-actin of human airway smooth muscle cells. Activation with PDGF led to an increase in the association of Raf-1 with cytoskeletal actin. Treatment of cells with the actin polymerization inhibitor latrunculin A (LAT-A), but not the microtubule depolymerizer nocodazole, inhibited the interaction of Raf-1 with actin in response to PDGF activation. Because abelson tyrosine kinase (Abl) is known to specifically regulate actin dynamics in smooth muscle, the role of Abl in modulating the coupling of Raf-1 with actin was also evaluated. Abl knockdown by RNA interference attenuated the association of Raf-1 with actin, which is recovered by Abl rescue. Treatment with LAT-A, but not nocodazole, inhibited the spatial redistribution of Raf-1 during PDGF activation. However, treatment with both LAT-A and nocodazole attenuated smooth muscle cell proliferation. Finally, Abl knockdown attenuated the redistribution of Raf-1 and cell proliferation, which were restored by Abl reexpression. The results suggest a novel mechanism that the interaction of Raf-1 with cytoskeletal actin is critical for Raf-1 redistribution and airway smooth muscle cell proliferation during activation with the growth factor.

Original publication

DOI

10.1165/rcmb.2012-0315OC

Type

Journal article

Journal

Am j respir cell mol biol

Publication Date

02/2013

Volume

48

Pages

172 - 178

Keywords

Actins, Base Sequence, Blotting, Far-Western, Bridged Bicyclo Compounds, Heterocyclic, Cell Proliferation, Cells, Cultured, Cytoskeleton, Gene Knockdown Techniques, Humans, Microtubules, Muscle, Smooth, Platelet-Derived Growth Factor, Protein Transport, Proto-Oncogene Proteins c-abl, Proto-Oncogene Proteins c-raf, RNA, Small Interfering, Thiazolidines, Trachea