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SHP-1 and PDK1 Form a Phosphotyrosine-Dependent Nucleo-Cytoplasmic Shuttling Complex: Implications for Differentiation

dc.contributor.advisorMousseau, Darrell D.en_US
dc.contributor.committeeMemberAnderson, Deborah H.en_US
dc.contributor.committeeMemberDyck, Lillian E.en_US
dc.contributor.committeeMemberLi, XinMinen_US
dc.creatorSephton, Chantelle Fionaen_US
dc.date.accessioned2007-06-28T11:37:51Zen_US
dc.date.accessioned2013-01-04T04:41:04Z
dc.date.available2009-07-03T08:00:00Zen_US
dc.date.available2013-01-04T04:41:04Z
dc.date.created2007en_US
dc.date.issued2007en_US
dc.date.submitted2007en_US
dc.description.abstractSHP-1 is a protein tyrosine phosphatase that often targets the phosphatidylinositol 3'-kinase (PI3K)/Akt signalling pathway. PI3K/Akt signalling regulates cell growth and survival, proliferation and differentiation. Growth factor-stimulated PI3K phospholipid production at the plasma membrane helps to recruit 3'-phosphoinositide-dependent protein kinase-1 (PDK1) and Akt, where PDK1 phosphorylates and activates the pro-survival kinase Akt.Tyrosine phosphorylation of PDK1 may regulate its function and, perhaps more importantly, its nuclear localization. Yet, it is unclear how PDK1 is imported into the nucleus as it does not contain a nuclear localization signal (NLS), although it does contain a nuclear export signal (NES). Interestingly, several tyrosines in PDK1 are targets for Src kinase and are putative target motifs for SHP-1, which does have an NLS.Hypothesis: SHP-1 and PDK1 form a tyrosine-dependent, nucleo-cytoplasmic shuttling complex. Removal of serum from C6 glioma cell cultures induces a platelet-derived growth factor receptor (PDGFR)-sensitive redistribution of PI3K lipid kinase activity to the nucleus. PDK1 tyrosine phosphorylation and its association with SHP-1 are also increased, as is the accumulation of both SHP-1 and PDK1 in the nucleus. Site-directed mutagenesis of tyrosine residues in PDK1 reveals that tyrosine 9 (Tyr9) and Tyr376 are important for the interaction of PDK1 with SHP1, whereas Tyr333 and Tyr 373 are not. Using pharmacological and genetic manipulations, it was demonstrated that SHP-1 and PDK1 shuttle between the nucleus and cytoplasm, and that the C-terminal-expressed NLS of SHP-1 facilitates shuttling, while dephosphorylation of PDK1 Tyr9 and Tyr376 regulates the rate of PDK1 (and by virtue of association, SHP-1) export from the nucleus. The SHP-1/PDK1 complex, which is constitutive in most cell lines, is functionally relevant as indicated by its requirement for NGF-induced differentiation of preneuronal cells to a neuronal phenotype.en_US
dc.identifier.urihttp://hdl.handle.net/10388/etd-06282007-113751en_US
dc.language.isoen_USen_US
dc.subjectnuclear localizationen_US
dc.subjectPDK1en_US
dc.subjectSHP-1en_US
dc.subjectPI3Ken_US
dc.subjectPC12en_US
dc.subjectdifferentiationen_US
dc.titleSHP-1 and PDK1 Form a Phosphotyrosine-Dependent Nucleo-Cytoplasmic Shuttling Complex: Implications for Differentiationen_US
dc.type.genreThesisen_US
dc.type.materialtexten_US
thesis.degree.departmentPsychiatryen_US
thesis.degree.disciplinePsychiatryen_US
thesis.degree.grantorUniversity of Saskatchewanen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophy (Ph.D.)en_US

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