Mechanism of filopodia formation in vascular endothelial cells

Abstract

By Alyssa Solano, Biochemistry

Advisor: Yoshi Odaka

Presentation ID: AM_D08

Abstract: Abnormal blood vessel development is implicated in several diseases including neoplasia, vascular anomaly, venous malformation, and various retinopathies. Current treatments aim to inhibit angiogenesis, the process by which new blood vessels form from existing blood vessels, but anti-angiogenic regimens have temporary and limited efficacy. This shortcoming justifies the need for new drugs with different targets. Angiogenesis requires the proliferation and migration of vascular endothelial cells (VECs) and the extension of filopodia, thin cellular protrusions that guide migration. While filopodia formation is a critical step in angiogenesis, its mechanism is not yet fully understood. This project seeks to define the mechanism of filopodia formation in VECs. Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that is part of two protein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The mTOR signaling pathway is active during angiogenesis, with mTORC1 promoting protein synthesis through various downstream effectors. Regulatory-associated protein of mTOR (Raptor) is an essential subunit of mTORC1, and preliminary data show that inactivating Raptor in VECs severely inhibits formation of filopodia. Ras-related C3 botulinum toxin substrate 1 (Rac1) is a Rho GTPase localized to the plasma membrane and known to regulate the actin dynamics involved in cytoskeleton remodeling. We have identified a possible interaction between Rac1 and mTOR, which could shed light on the molecular mechanism that creates the filopodial phenotype observed when Raptor is inactivated.