Abstract 705: Epha2 Ligand-dependent And Ligand-independent Signaling In Vascular Smooth Muscle Cell Proliferation And Migration

Abstract

During atherosclerotic plaque formation, vascular smooth muscle cells (VSMCs) undergo phenotypic modulation from a contractile, quiescent phenotype to a proliferative and synthetic phenotype, allowing VSMCs to deposit form a protective fibrous cap to stabilize the cap through extracellular matrix assembly. Our lab discovered a novel role for the receptor tyrosine kinase EphA2 in SMC phenotypic modulation and proliferation both in vitro and in vivo . In many cancer models, EphA2 can act as a tumor promoter in the absence of ligand and a tumor suppressor in the presence of its ephrinA1 ligand. Therefore, we sought to determine the role of ligand-dependent and ligand-independent signaling in VSMC function. While EphA2 expression is required for maximal VSMC proliferation and migration, EphA2 ligation with ephrinA1 inhibits VSMC proliferation (associated with diminished Erk1/2 and Akt activation) and migration. While ligand treatment induces EphA2 tyrosine phosphorylation, treating VSMCs with serum promotes robust S897 phosphorylation (marker for ligand-independent signaling) specifically through RSK2, whereas no role was found for other described S897 kinases (e.g. Akt, RSK1). EphA2 Ser897 phosphorylation specifically localizes to lamellipodia in VSMCs treated with serum, and blocking RSK2-dependent S897 phosphorylation significantly inhibited VSMC migration but did not affect VSMC proliferation. Taken together, these data suggest that VSMC EphA2 ligation suppresses proliferation and migration, whereas RSK2-dependent EphA2 Ser897 phosphorylation in the absence of ligand promotes VSMC migration, and EphA2 expression likely enhances VSMC proliferation through a ligand-independent response independent of S897 phosphorylation.