Date on Master's Thesis/Doctoral Dissertation

8-2015

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

Beverly, Levi

Committee Co-Chair (if applicable)

Sisking, Leah

Committee Member

Sisking, Leah

Committee Member

Ceresa, Brian

Committee Member

Clark, Geoffrey

Committee Member

Roman, Jesse

Subject

Protein-tyrosine kinase

Abstract

Receptor Tyrosine Kinases (RTK’s) like EGFR, Insulin Receptor, IGF1R and others mediate growth, proliferation and balance between apoptosis and survival. Dysregulation of RTK activity has been identified in a wide range of cancers and contributes to initiation, progression and metastasis of tumors. Ubiquilins (UBQLN) are fairly novel proteins and are studied mostly in the field of neurodegenerative disorders. Our laboratory recently discovered a link between UBQLN1 function and tumorigenesis. UBQLN1 is lost in about 50% of non-small cell lung cancer (NSCLC) cases. We have identified an interaction between UBQLN1 and IGF1R. Furthermore, UBQLN1 regulates activity of IGF1R and EGFR. Following loss of UBQLN1 in lung adenocarcinoma cells, there is decreased expression of IGF1R and EGFR at the mRNA and protein levels. Fewer receptors are available for ligand binding on plasma membrane of UBQLN1 deficient cells. Despite this decrease in total number of receptors, the ratio of active:inactive (phosphorylated:non-phosphorylated) receptor is higher in cells that have loss of UBQLN1 function. We conclude that UBQLN1 is essential in normal regulation of RTKs. Loss of UBQLN1 leads to persistent stimulation of IGF1R and EGFR which may contribute to transforming events in UBQLN1 deficient cells. Understanding the role of UBQLN1 in regulating receptor tyrosine kinase activity can facilitate development of pharmacological drugs targeting novel pathways in diseases that have altered function of UBQLN1.

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