PHOSPHORYLATION-INDUCED CONFORMATIONAL CHANGES OF PTEN REVEALED BY PROTEIN SEMISYNTHESIS

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dc.contributor.advisorCole, Philip A.en_US
dc.contributor.committeeMemberGabelli, Sandra B.en_US
dc.contributor.committeeMemberDevreotes, Peter N.en_US
dc.contributor.committeeMemberAmzel, L. Marioen_US
dc.contributor.committeeMemberRaben, Daniel M.en_US
dc.creatorBolduc, David Michaelen_US
dc.date.accessioned2014-12-23T04:39:37Z
dc.date.available2014-12-23T04:39:37Z
dc.date.created2014-05en_US
dc.date.issued2013-10-01en_US
dc.date.submittedMay 2014en_US
dc.description.abstractPTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressing lipid phosphatase that negatively regulates the PI3K/PTEN/AKT signaling pathway by dephosphorylating the lipid second messenger PIP3. PTEN is one of the most frequently mutated genes in cancer and loss of PTEN function is found in many cancer types. There are a variety of mechanisms within cells by which PTEN is regulated. One mode of regulation is through a cluster of phosphorylations on PTEN’s C-terminal regulatory tail at amino acids Ser380, Thr382, Thr383 and Ser385. Phosphorylation of this cluster has been proposed to reduce PTEN’s ability to bind to membranes and access its substrate, though the exact mechanism by which this occurs is poorly understood. To study the regulatory affects of phosphorylation at this regulatory cluster we have employed expressed protein ligation to generate semisynthetic PTEN in its phosphorylated and unphosphorylated forms. Using a variety of biochemical and biophysical techniques we have found that relative to its unphosphorylated form, phosphorylated PTEN binds to phospholipid membranes with lower affinity which results in a decrease in its catalytic activity. This decrease in membrane binding ability and catalytic activity is accomplished through a phosphorylation induced conformational change in the PTEN protein. When phosphorylated, the C-terminal tail of PTEN binds to the membrane binding surface of the C2 domain, thereby reducing PTEN’s ability to interact with membranes and access its substrate.en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.urihttp://jhir.library.jhu.edu/handle/1774.2/37060
dc.languageen
dc.publisherJohns Hopkins University
dc.subjectPTENen_US
dc.subjectPhosphorylationen_US
dc.titlePHOSPHORYLATION-INDUCED CONFORMATIONAL CHANGES OF PTEN REVEALED BY PROTEIN SEMISYNTHESISen_US
dc.typeThesisen_US
dc.type.materialtexten_US
thesis.degree.departmentPharmacology and Molecular Sciencesen_US
thesis.degree.disciplinenot listeden_US
thesis.degree.grantorJohns Hopkins Universityen_US
thesis.degree.grantorSchool of Medicineen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePh.D.en_US
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