All ETDs from UAB

Advisory Committee Chair

Joanne E Murphy-Ullrich

Advisory Committee Members

Andra Frost

James Hagood

Louis Justement

Danny Welch

Anne Woods

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Calreticulin (CRT), classically known for its chaperone functions in the endoplasmic reticulum and as a calcium regulator, also is found on the cell surface and in the extracellular matrix. It is involved in many cellular processes including signaling, adhesion, migration, apoptotic cell clearance, gene regulation, and production of a fibronectin matrix. CRT has been suggested to play a role in wound healing and fibrosis. Therefore, these studies investigated the role of CRT in collagen production, an important extracellular matrix molecule in wounding and fibrosis. We demonstrated that CRT regulates collagen through transcription, secretion, and processing. We also investigated the role of cell surface CRT on signaling through its co-receptor, low density lipoprotein receptor-related protein-1 (LRP1), in response to thrombospondin 1 (TSP1). TSP1 signaling through CRT and LRP1 causes focal adhesion disassembly, cell migration, and anoikis resistance. We found that TSP1 causes LRP1 phosphorylation, which may contribute to its cell signaling capabilities. TSP1, CRT, and LRP1 also have been implicated in cancer development. Therefore, we explored the role of TSP1 binding to CRT and signaling through LRP1 in breast cancer invasion. Our findings do not support a role for TSP1 signaling through CRT and LRP1 in breast cancer invasion. In conclusion, these studies demonstrate that CRT regulates fibrillar collagens. In addition, TSP1 signaling through cell surface CRT and LRP1 induces tyrosine phosphorylation of LRP1.

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