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You searched for +publisher:"University of North Carolina" +contributor:("Alan, Jamie"). One record found.

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University of North Carolina

1. Alan, Jamie. TYROSINE KINASE MODULATION OF TRAFFICKING AND BIOLOGICAL FUNCTIONS OF THE ATYPICAL RHO GTPASE, WRCH-1.

Degree: Pharmacology, 2010, University of North Carolina

Wrch-1 is an atypical Rho family small GTPase with roles in oncogenic transformation, epithelial cell morphogenesis, osteoclastogenesis, and migration. We have shown previously that Wrch-1 membrane localization and biological functions are modulated by reversible addition of a palmitate at its C-terminal membrane targeting domain. Most GTPases have at least two membrane targeting signals but no additional signals for Wrch-1 were known. We now show that the subcellular localization of Wrch-1 is responsive to growth factors contained in serum and is modulated by Src-mediated tyrosine phosphorylation. Upon stimulation with serum, Wrch-1 became phosphorylated on the evolutionarily conserved residue Y254 in its C-terminal membrane-targeting region, and relocalized from plasma membrane (PM) to endosomal compartments. Wrch-1 is known to interact with the adapter proteins Grb2 and Nck that in turn interact with growth factor receptor tyrosine kinases. We therefore next evaluated Wrch-1 modulation by RTK ligands such as EGF or PDGF. Wrch-1 was tyrosine phosphorylated in response to EGF treatment in time- and dose-dependent manner, and this was blocked by pretreatment with pharmacological inhibitors of either Src or EGFR. Wrch-1 relocalized rapidly from PM to endosomes upon EGF stimulation, similar to serum stimulation. Wrch-1 was phosphorylated at Y254 downstream of constitutively active forms of EGFR and HER2, including the deletion mutant EGFRvIII. Functionally, the phosphodeficient Wrch-1 mutant Y254F was enhanced in Wrch-1-mediated migration, cystogenesis and transformation. Thus, EGFR, Src dependent, C-terminal tyrosine phosphorylation of Wrch-1 may represent a novel feedback mechanism to down-regulate its activity. Consistent with this hypothesis, Wrch-1-GTP and effector activation are decreased after serum stimulated tyrosine phosphorylation and subsequent endosomal relocalization. Also, we observed that phosphodeficient Wrch-1 remained GTP-bound and plasma membrane-localized in the presence or absence or serum, whereas a phosphomimetic mutant remained GDP-bound and localized at endosomes. Thus, EGFR-mediated, Src-dependent C-terminal tyrosine phosphorylation of Wrch-1 may be a negative feedback mechanism to regulate both the trafficking and biological activities of Wrch-1. C-terminal tyrosine phosphorylation represents a new paradigm in posttranslational control of small GTPase localization and biological function. Advisors/Committee Members: Alan, Jamie, Cox, Adrienne, Der, Channing, Schaller, Michael D., Johnson, Gary, Rogers, Stephen.

Subjects/Keywords: School of Medicine; Department of Pharmacology

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APA (6th Edition):

Alan, J. (2010). TYROSINE KINASE MODULATION OF TRAFFICKING AND BIOLOGICAL FUNCTIONS OF THE ATYPICAL RHO GTPASE, WRCH-1. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:afbc9ce5-f21d-4707-8744-357971e1eb3b

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Alan, Jamie. “TYROSINE KINASE MODULATION OF TRAFFICKING AND BIOLOGICAL FUNCTIONS OF THE ATYPICAL RHO GTPASE, WRCH-1.” 2010. Thesis, University of North Carolina. Accessed October 26, 2020. https://cdr.lib.unc.edu/record/uuid:afbc9ce5-f21d-4707-8744-357971e1eb3b.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Alan, Jamie. “TYROSINE KINASE MODULATION OF TRAFFICKING AND BIOLOGICAL FUNCTIONS OF THE ATYPICAL RHO GTPASE, WRCH-1.” 2010. Web. 26 Oct 2020.

Vancouver:

Alan J. TYROSINE KINASE MODULATION OF TRAFFICKING AND BIOLOGICAL FUNCTIONS OF THE ATYPICAL RHO GTPASE, WRCH-1. [Internet] [Thesis]. University of North Carolina; 2010. [cited 2020 Oct 26]. Available from: https://cdr.lib.unc.edu/record/uuid:afbc9ce5-f21d-4707-8744-357971e1eb3b.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Alan J. TYROSINE KINASE MODULATION OF TRAFFICKING AND BIOLOGICAL FUNCTIONS OF THE ATYPICAL RHO GTPASE, WRCH-1. [Thesis]. University of North Carolina; 2010. Available from: https://cdr.lib.unc.edu/record/uuid:afbc9ce5-f21d-4707-8744-357971e1eb3b

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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