RalA signal transduction

Duke University, Durham NC

Investigators

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Abstract

DESCRIPTION (provided by applicant): A quarter or more of all human cancers have an oncogenic mutation in one of the RAS genes, rendering the encoded protein constitutively active, which promotes tumorigenesis. While oncogenic Ras has so far defied clinical inhibition, studies of signaling through two of its most notorious effectors, RAF and PI3K, have led to new antineoplastic drugs. There is, however, a third major effector of oncogenic Ras involved in cancer that is far less studied, namely RalGEFs that activate the two Ras like GTPases RalA and RalB. Broadly speaking, RalA is important in transformation, tumor initiation, and maintenance whereas RalB plays a more prominent role in cell migration, invasion, and metastasis. This difference in function can be ascribed, at least in part, to an Aurora A phosphorylation site in RalA that is absent in RalB. Moreover, phosphorylation of this site on RalA by Aurora A is critical for oncogenic Ras tumorigenesis, and both high Aurora A expression and RAS mutations occur together in a number of human cancers. Taken together, these results suggest that the combined activation by oncogenic Ras and phosphorylation by up-regulated Aurora A of RalA promotes tumorigenesis. In terms of the underlying mechanism of how these two events drive tumor development, we discovered that activation and phosphorylation of RalA re-localizes the protein with its effector RalBP1 to mitochondria to induce fission. This novel discovery provides the first direct molecular link between Ras oncogenesis through RalA and mitochondrial function during tumorigenesis. To better understand this relationship we propose to determine in aim 1, the mechanism by which RalA is activated to promote fission, in aim 2, what other kinases phosphorylate RalA and the consequences thereof, in aim 3, the mechanism by which RalBP1 induces fission to promote tumorigenesis, and finally in aim 4, the consequence of blocking phosphorylation of endogenous RalA on cancer development in vivo. Completion of these aims will elucidate the molecular mechanism by which RalA signaling promotes mitochondrial fission, and the effect of this signaling on cancer development in vivo.