Regulation of p190RhoGEF by Activated Rho and Rac GTPases: Amplification and Crosstalk

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dc.contributor.advisorTaussig, Ronalden
dc.contributor.committeeMemberAlto, Nealen
dc.contributor.committeeMemberYu, Hongtaoen
dc.contributor.committeeMemberSternweis, Paul C.en
dc.creatorDada, Olugbenga Adesolaen
dc.creator.orcid0000-0001-9847-7197
dc.date.accessioned2019-06-03T19:57:18Z
dc.date.available2019-06-03T19:57:18Z
dc.date.created2017-05
dc.date.issued2017-04-14
dc.date.submittedMay 2017
dc.date.updated2019-06-03T19:57:18Z
dc.description.abstractThe Rho family of monomeric GTPases regulates a wide range of cellular processes including cytoskeletal structure, motility, cell division, gene transcription, vesicular transport, and various enzymatic activities. Activation of Rho proteins largely depends on Rho Guanine nucleotide Exchange Factors (RhoGEFs), which catalyze the exchange of GTP for GDP on Rho. For classical RhoGEFs, the exchange activity resides in a Dbl homology (DH) domain, which is linked to a pleckstrin homology (PH) domain that subserves various functions. We have crystallized and solved structures of the PH domain from p190RhoGEF bound to either RhoA•GTP or Rac1•GTP. The interfaces between activated Rac1 or RhoA with the PH domain utilize the same hydrophobic surface on the PH domain. Similar to RhoA, activated Rac1 interacts with the PH domain via its effector-binding surface albeit burying less surface area than the interaction of RhoA with the PH domain. Consequently, the PH domain of p190RhoGEF has a higher affinity for RhoA than Rac1. Both activated RhoA and Rac1 can stimulate exchange of nucleotide on RhoA by localization of the p190RhoGEF to the substrate, RhoA•GDP, in vitro; mutations of key hydrophobic residues in the PH domain abolish this stimulation. Among members of the homologous Lbc subfamily of RhoGEFs, p190RhoGEF exhibited the greatest capacity for regulation by Rac1. While interaction of RhoA with the PH domain provides a mechanism for direct positive feedback, the novel interaction of activated Rac1 with the PH domain of p190RhoGEF reveals a potential mechanism for cross-talk regulation between the Rho and the Rac signaling pathways.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1103324462
dc.identifier.urihttps://hdl.handle.net/2152.5/6617
dc.language.isoenen
dc.subjectBlood Proteinsen
dc.subjectGuanine Nucleotide Exchange Factorsen
dc.subjectPhosphoproteinsen
dc.subjectPleckstrin Homology Domainsen
dc.subjectrac1 GTP-Binding Proteinen
dc.subjectrhoA GTP-Binding Proteinen
dc.titleRegulation of p190RhoGEF by Activated Rho and Rac GTPases: Amplification and Crosstalken
dc.typeThesisen
dc.type.materialtexten
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCell Regulationen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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