A role for focal adhesion kinase in vascular smooth muscle cell proliferation, migration and differentiation
by Smith, Liisa Sundberg, Ph.D., THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL, 2007, 2036 pages; 3272708

Abstract:

Smooth muscle cells (SMC) are involved various vascular diseases, such as atherosclerosis, restenosis following balloon angioplasty and following venous bypass grafts. During the development of these vascular diseases and during normal vascular development, numerous changes occur within the vessel environment that enables SMC to phenotypically modulate between a contractile phenotype and a proliferative phenotype. The remodeling of the extracellular matrix, an increase in growth factors and contractile agonists have all been shown to initiate signaling pathways leading to an increase in SMC proliferation, migration, and differentiation. The tyrosine kinase, Focal Adhesion Kinase (FAK) plays a major role in the integration of the signals transmitted from these extracellular cues. The aim of this dissertation was to determine the SMC functions that are regulated by FAK. To address this goal, I evaluated two prominent signaling pathways; the Ras/Raf/Mek/Erk and Pi3-kinase/Rac/Pak/JNK cascades, both have been shown to be required for cell growth and motility in certain cell types. The data presented herein shows that FAK activity is required for PDGF-, AngII- and adhesion-mediated Rac1 activation. The p21-activated kinases (PAK) are downstream targets of various signaling cascades including PDGF-BB and integrins and are effectors for the GTPases Rac1 and Cdc42. Recently, it was shown that PAK activity is required for maximal activation of the canonical Ras/Raf/Mek/ERK MapKinase signaling cascade. Therefore, I aimed to determine the role of PAK within the ERK signaling cascade and found that adhesion-dependent activation of PAK may enhance growth factor-stimulated signaling and PAK may serve as a scaffold for the Raf/Mek/Erk signaling cascade in SMC. I also sought to determine if FAK activity plays a role SMC phenotypic modulation. I found that deletion of FAK or inactivation of FAK by FRNK (FAK related non-kinase) expression causes a significant increase SMC-specific gene expression. Additionally, the LIM protein, leupaxin, associates with FAK and can translocate from focal adhesions to the nucleus leading to increased SMC marker gene transcription. These data indicate that FAK may serve as a necessary regulator of SMC phenotypic modulation during vasculogensis, where FAK activation promotes a dedifferentiated proliferative phenotype and FAK inactivation induces a switch to a differentiated contractile phenotype.

 
AdviserJoan M. Taylor
SchoolTHE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
SourceDAI/B 68-07, p. , Nov 2007
Source TypeDissertation
SubjectsCellular biology; Pathology
Publication Number3272708
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