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Title page for ETD etd-07192013-151521


Type of Document Dissertation
Author Palmer, Trenis Duwon
URN etd-07192013-151521
Title Regulation of Tumor Cell Metastasis by CD151
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Alissa Weaver Committee Chair
Donna Webb Committee Member
Jeffery Davidson Committee Member
Roy Zent Committee Member
Sarki Abdulkadir Committee Member
Keywords
  • cell migration
  • metastasis
  • CD151
  • ALCAM
Date of Defense 2013-06-13
Availability unrestricted
Abstract
Recently our lab has demonstrated that clustering of the tetraspanin CD151 on the surface of tumor cells is capable of inhibiting cell migration and cancer metastasis. As a member of the tetraspanin superfamily CD151 associates with a number of proteins on the cell surface and functions as a molecular scaffolding protein when clustered into protein rich complexes known as Tetraspanin Enriched Microdomains (TERM). Treatment of tumor cells with the anti-CD151 monoclonal antibody (MAb) 1A5 promotes the localization of CD151 to the areas of cell-cell contact to promote adhesion and inhibit migration and metastasis through TERM formation. Due to the published associations with the laminin binding integrins (primarily α3β1), combined with the ability of CD151 to regulate α3β1-mediated adhesion, we hypothesized that it would be involved in the inhibition of migration and metastasis mediated by the clustering of CD151. Using a number of experimental techniques we present data demonstrating that 1A5 recognizes the integrin-association epitope of CD151 and binds to integrin free CD151 (CD151free). Additionally, we demonstrate that the expression of integrin α3 is not required for the ability of CD151 to control motility. Although the role of CD151free in the regulation of tumor cell migration and metastasis is not fully understood, we found it to be increasingly present in the tumor tissue of patients with aggressive prostate cancer. In fact, CD151free staining was an independent prognostic indicator of survival. It is possible that CD151free promotes metastasis, however, more research is necessary to test that hypothesis. The demonstration that that α3β1 is not functionally involved in the regulation of migration by CD151 suggests that there are functions of CD151 related to motility and adhesion that are independent of integrin associations. By proteomic analysis we elucidated the components of the CD151TERM complex and pulled down the novel CD151-associated protein ALCAM/CD166. Functionally, we demonstrate that ALCAM is required for the inhibition of migration as a component of the CD151-TERM complex. Mechanistically, the CD151/ALCAM immobility complex signals through Protein Kinase Cα to activate the small GTPase Rap1A to control motility. The inhibition of migration through Rap1A is presumably through an increase in cell-matrix adhesion. Ultimately, sustained activation of Rap1 is sufficient to inhibit metastasis. This thesis defines the role of CD151 as a molecular integrator of migration and regulator of metastasis through its ability to control both cell-cell and cell-matrix adhesion.

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