Roles for G Proteins in Wnt/Frizzled Signaling

Duke University, Durham NC

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Abstract

The Wnt family of proteins are secreted signaling molecules that regulate a number of critical developmentalprocesses,includingcellularproliferationand differentiation. Moreover,aberrant activation of the Wnt signaling pathway has been shown to be an important component in oncogenesis. Wnt signaling is very complex and is initiated by a family of transmembrane heptahelicalreceptorsknownas Frizzled, whichare mostcloselyrelatedto the familyof G protein coupled-receptors.DespiteevidenceimplicatingG proteinsin Wnt/Frizzledsignaltransductiont,he precisemechanismby whichFrizzledreceptorschoosedownstreamtargetsandtransmitsignalsto them isstillunclear. Inthisapplication,I proposeto identifyspecificFrizzled/Gproteininteractions to test the hypothesisthat Frizzledreceptorsare, infact, G protein-coupledreceptors. In addition,I willattemptto definethe role of G proteinsin determiningWnt/Frizzledsignalingpathwaychoices and in linkingFrizzledto knowndownstreamtargetmoleculessuch as Axin. The proposedproject will be undertakenwiththe mentorshipof Dr. PatrickJ. Casey and Dr. RobertJ. Lefkowitzandwith the support of the Department of Pathology at Duke University. My background in protein biochemistryand G proteinsignalingprovidesa solidfoundationfor initiatingthese studies. This awardwillallowme to developskillsnecessarytoprogressto the studyof more biologicalaspects ofcell regulationandwillfacilitatemytransitiontoan independentinvestigator.