Angiotensin II (AngII) is a potent stimulator of vascular hypertrophy which is mediated through the Ang II typel receptor (AT1R) in vascular smooth muscle cells (VSMCs). Many of its important outputs result from transactivation of the EGF receptor (EGF-R), which requires initial activation of cSrc and which is dependent on reactive oxygen species (ROS) derived from NAD(P)H oxidase (Nox). Caveolin-enriched lipid rafts (CE/LRM) are specialized membrane microdomains where signaling molecules such as EGFR are compartmentalized via interacting with caveolin-1 (Cav1). We showed that Ang II promotes AT1R trafficking into CE/LRM, which is required for transactivation of EGF-R and egress of EGF-R from the CE/LRM, resulting in colocalization of pY-EGFR with pY14Cav1 at focal adhesions. We also found that AT1R migration into CE/LRM is dependent on ROS, cSrc, microtubules/actin cytoskeleton and Cav1;however, underlying, organizing molecular mechanisms are poorly understood. cAbl is a F-actin binding non-receptor tyrosine kinase that links receptor tyrosine kinase and actin remodeling. Cav1 is a major ROS-dependent tyrosine phosphorylation target of cAbl. We show that AT1R activates cAbl in VSMCs and mouse aorta, and promotes cAbl binding to the AT1R, which are dependent on ROS, cSrc and Cav1. Preliminary data led us to hypothesize that cAbl functions as a central organizer for ROS, Cav1 and actin cytoskeleton-dependent AT1R trafficking and signaling, which may contribute to vascular hypertrophy. To test this hypothesis, AIM1 will characterize the interaction of AT1R and cAbl, and define the mechanisms of cAbl activation by Ang II.
AIM2 will explore the mechanisms by which cAbl is activated by Nox-derived ROS with focusing on oxidative inactivation of SHP-2 which binds directly to AT1R and negatively regulates cSrc.
AIMS will explore the molecular mechanisms by which cAbl mediates Ang ll-stimulated AT1R migration into CE/LRM, formation of pY-EGF-R signaling complex at focal adhesions and hypertrophy with focus on cAbl downstream targets, cortactin and Y14Cav1.
AIM4 will assess the funcional role of cAbl in Ang ll-induced vascular hypertrophy in vivo. Knockout mice and cells, live cell imaging, cell fractionation, protein-protein interaction and molecular biological aanlysis will be used. These studies should provide new insights into the organization of Ang II signaling and identify potential new targets for novel therapeutic apporaches to cardiovascular diseases.
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