PDGF Signaling in Urinary Tract Smooth Muscle

Children'S Hospital Boston, Boston MA

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Abstract

Tissue remodeling in the urinary tract is not understood in mechanistic terms at even the most superficial level. This project originates from observations in our laboratory that appear to shed light on one or more critical signaling pathways that may be releveant to tissue-specific mechanisms of fibromuscular remodeling in the hollow organs of the lower urinary tract (ureter, bladder and urethra). We hypothesize that some signals that trigger smooth muscle cell (SMC) growth in the urinary tract are processed through cholesterol-rich plasma membrane domains known as lipid rafts. The lipid compartment of cell membranes has recently been revealed to be a mediator of cell signals leading to discrete activation of downstream signal transduction cascades. The invaginated membrane compartments known as "caveolae" are a specialized form of lipid raft. Our findings are consistent with recent reports in the literature suggesting that these subcellular compartments may be modified in certain urologic disease processes, such as bladder instability, and may contain marker proteins that might ultimately prove to be of clinical utility in diagnosis, disease prognosis and further mechanistic investigations. We have identified the SMC mitogen, platelet-derived growth factor-BB (PDGF-BB), as a tissue-selective growth factor in cell culture studies of urinary tract SMC. Our findings point to this soluble factor, and pathways downstream from it, as a potentially physiologically relevant component of the tissue remodeling mechanism in ureteral and bladder SMC. Our group and others have linked PDGF signaling to lipid rafts/caveolae. Our observations of the intriguing biological activities of PDGF-BB in mediating cell growth led us to the finding that this growth factor is a potent activator of the PI3-kinase/Akt signaling pathway in urinary tract SMC, and that this mechanism resembles a signaling system activated in response to stretch. Lastly, we present evidence that the serine-threonine kinase, Akt, an important mediator of growth and survival signals in a variety of cell types, functions by a lipid raft-dependent mechanism. Based on these findings, we propose the following specific aims: Aim 1: Determine the role of lipid rafts/caveolae in mediating PDGF- and stretch-dependent signals in urinary tract SMC. Aim 2: Determine the role of lipid rafts/caveolae in activation of Akt by PDGF-BB and stretch. Aim 3: Identify lipid raft-resident proteins that participate in the PDGF/stretch--->Akt signaling mechanism.