Date of Award

January 2015

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Medicinal Chemistry and Molecular Pharmacology

First Advisor

Robert L Geahlen

Committee Member 1

Tony R Hazbun

Committee Member 2

R. Claudio Aguilar

Abstract

Spleen Tyrosine Kinase (Syk) is a 72 kDa non-receptor protein-tyrosine kinase. It plays an essential role in B cell development and signaling downstream of many immune receptors. However, its expression is not limited to just B cells, as it has been shown to play a functional role in signaling in many other hematopoietic cell types such as thymocytes, mast cells, macrophages and natural killer cells. Its expression and roles have expanded since its original discovery; and it has now been associated with epithelial tissues as well as tumor progression and prognosis. A particular interest has focused on Syk and its suggested tumor suppressor role in various epithelial-based carcinomas. Loss of Syk expression both at the mRNA and protein level in breast cancer has been associated with loss of cell-cell adherence and increased mobility and invasiveness. Similar effects have been observed with overexpression of protein arginine methyltransferase five (PRMT5) and seven (PRMT7) in breast cancer, indicating a new potential mechanism by which Syk may regulate the ability of cancer to metastasize. Western blot analysis has demonstrated Syk's ability to alter the di-symmetric methylation of proteins catalyzed by PRMT5. PRMT5 and Syk were found to reside in a complex with one another. Further analysis by immunoprecipitation indicated that the formation of this Syk-PRMT5 complex was dependent on nucleolin expression. A downstream substrate of PRMT5, SUPT5H, also displayed the ability to form a complex with Syk. SUPT5H is a component of a large complex that regulates mature B cell class switching. A component of this complex, LEO1, was also shown to interact with Syk through immunoprecipitation. These results suggest Syk interacts with the methyltransferase PRMT5 and some of its substrates. Furthermore, this study indicates that Syk is interacting with components of a complex that regulates class switch recombination.

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