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The role and regulation of mTORC2 in cell migration-undergrad

Sponsored by National Institute of General Medical Sciences

$7.4K Funding
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PROJECT SUMMARY The directed migration of cells is an important cellular behavior key to normal physiology and deregulatedin disease including cancer. Yet how cells direct their movements in response to migration cues is notunderstood. The mechanistic Target of Rapamycin Complex 2 (mTORC2) plays an evolutionarily conservedrole in regulating the actin cytoskeleton and controlling the migration of cells. mTORC2 is one of twomultiprotein signaling complexes formed by the mTOR kinase. mTORC1 is a key regulator of cell growth andproliferation and its regulation and signaling pathway are well described. Much less is known about mTORC2but recent research revealed a role for mTORC2 in promoting cancer cell migration and tumor dissemination.The ability to target the mTORC2 pathway in cancer therapy however is greatly hampered by a lack ofmechanistic insight into how mTORC2 is activated regulated and signals to the cell motility machinery. Weaim to address this knowledge gap by identifying the key molecular mechanisms that direct mTORC2 activityand function in cell migration. Recently we discovered that two Ras family GTPases Ras and Rap1 bindmTOR and the mTORC2 component RIP3/SIN1 respectively and control mTORC2 activity in theexperimental model Dictyostelium discoideum. Importantly our preliminary data indicate that these mTORC2regulatory mechanisms are conserved in human cells. Our overall objective is to determine the mechanismand role of Ras and Rap1-mediated regulation of mTORC2 activity and function in cell migration. Our centralhypothesis is that Ras and Rap1 independently regulate mTORC2 in response to a migration signal throughdistinct interactions with components of mTORC2 thereby controlling mTORC2's signaling functions in cellmigration and playing a key role in promoting cancer cell migration. We will test our hypothesis in three specificaims. In Aim 1 we will take advantage of the mTOR interaction with the Dictyostelium Ras protein RasC thatwe have identified to define the mechanism and role of Ras-mediated mTORC2 regulation in cell migrationusing Dictyostelium as experimental model. In Aim 2 we will identify the role of Rap1 in regulating mTORC2function in cell migration using prototypical human epithelial cells as experimental model. In Aim 3 we willdefine the mTORC2 pathway controlling breast cancer cell migration applying our findings from themechanistic studies performed in Aim 1 and Aim 2 to specifically interrogate the role of Ras- and Rap1-regulated mTORC2 in promoting the migration of breast cancer cells. Altogether the proposed work will lead tothe description of novel molecular mechanisms involved in regulating mTORC2 and cell migration includingthat of cancer cells which will provide innovative opportunities for the development of therapeutic strategies forinhibiting the migration of cancer cells in metastasis. Furthermore our findings will also advance thedevelopment of treatments for other diseases that involve the pathological migration of cells includingcardiovascular inflammatory and autoimmune disorders in which mTOR pathways play important roles.