Molecular mechanisms of TMEFF2 action in Prostate Cancer

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dc.contributor.advisorRuiz-Echevarria, Mariaen_US
dc.contributor.authorChen, Xiaofeien_US
dc.contributor.departmentBiochemistry and Molecular Biologyen_US
dc.date.accessioned2014-01-28T12:54:16Z
dc.date.available2015-02-02T17:10:40Z
dc.date.issued2013en_US
dc.description.abstractThe transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is an evolutionarily conserved type I transmembrane protein expressed in the embryo and limited adult tissues, mainly the brain and the prostate. The ectodomain of TMEFF2 can be cleaved from the membrane in an ADAM17/gamma-secretase-dependent fashion and consists of an epidermal growth factor-like motif and two follistatin motifs. The cytoplasmic portion contains a potential G protein-activating (GA) domain. Given its elevated expression in primary and metastatic prostate cancer, TMEFF2 has been implicated to play a role in this disease. However, the exact biological function of TMEFF2 is rather controversial, with conflicting reports supporting both tumor-suppressing and growth-promoting activities of TMEFF2.   In the present study, we demonstrate a dual mode of action for TMEFF2. Ectopic expression of wild-type full-length TMEFF2 inhibits monolayer and anchorage-independent cell growth, cellular invasion and migration, and increases cellular sensitivity to apoptosis. In contrast, expression of TMEFF2 ectodomain or addition of conditioned medium containing the ectodomain increases cell proliferation, in line with previous results using recombinant TMEFF2 ectodomain protein. Furthermore, we investigate the molecular mechanisms involved in the function of TMEFF2. TMEFF2 interacts with sarcosine dehydrogenase and modulates cellular levels of sarcosine, a differential metabolite that increases during prostate cancer progression. The tumor suppressor activity of TMEFF2 correlates in part with its ability to modulate sarcosine levels. Moreover, TMEFF2 expression decreases prostate cancer cell spreading and migration, particularly on vitronectin, with a concomitant decrease in focal adhesion and stress fiber formation. Consistently, TMEFF2 inhibits RHOA activation - RHOA activation is known to induce stress fiber formation -- and downregulates expression of several integrins including beta1 and the major receptor for vitronectin -- alphavbeta3. All these effects require the presence of the GA domain, as expression of a TMEFF2 mutant lacking the GA domain does not affect RHOA activation or integrin expression. Finally, we show that different forms of TMEFF2 differentially regulate AKT and ERK activation. While the full-length TMEFF2 protein promotes ERK phosphorylation in response to growth factors EGF and PDGF-AA, the ectodomain activates AKT and inhibits ERK phosphorylation, which may contribute to the distinct cellular responses of tumor suppression or proliferation. Altogether, these data provide significant knowledge on the molecular mechanisms of TMEFF2 action, shedding light on the seemingly conflicting roles of various TMEFF2 forms.  en_US
dc.description.degreePh.D.en_US
dc.format.extent154 p.en_US
dc.format.mediumdissertations, academicen_US
dc.identifier.urihttp://hdl.handle.net/10342/4314
dc.language.isoen_US
dc.publisherEast Carolina Universityen_US
dc.subjectMolecular biologyen_US
dc.subjectOncologyen_US
dc.subjectBiology, Molecular
dc.subject.meshProstatic Neoplasms--pathology
dc.subject.meshProstatic Neoplasms--therapy
dc.subject.meshReceptors, Androgen--physiology
dc.subject.meshAndrogens--physiology
dc.subject.meshCell Transformation, Neoplastic
dc.subject.meshCell Survival
dc.subject.meshCell Proliferation
dc.subject.meshIntracellular Signaling Peptides and Proteins
dc.subject.meshSignal Transduction
dc.subject.meshMembrane Proteins
dc.titleMolecular mechanisms of TMEFF2 action in Prostate Canceren_US
dc.typeDoctoral Dissertationen_US

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