UC San Diego

GOLPH3 is an oncogene that is amplified in many different tumor types and its overexpression often correlates with poor survival. Previously known functions of GOLPH3 include its participation in secretory trafficking from the Golgi and enhancing cell survival following exposure to DNA damaging agents. In view of the fact that standard cancer chemotherapy commonly employs DNA damaging agents, the survival benefit conferred to cells by GOLPH3 overexpression provides a likely explanation for the correlation of high GOLPH3 expression with poor patient survival. However, this function of GOLPH3 in promoting cell survival seems insufficient to explain why GOLPH3 is an oncogene in the first place. It has been observed that GOLPH3 expression can modulate the strength of growth factor signaling, and inhibition of growth factor signaling ablates GOLPH3’s transforming ability, but the mechanism for how GOLPH3 modulates growth factor signaling remains unclear. Chapter 2 of the dissertation documents a systematic investigation into the role of GOLPH3 in growth factor signaling and traces the requirement for GOLPH3 to the level of regulating growth factor receptors themselves. Both GOLPH3 and the unconventional myosin, MYO18A, which mediates the Golgi function of GOLPH3, are each required for growth factor signaling. Depletion of either GOLPH3 or MYO18A retains growth factor receptors at the Golgi, reducing their levels at the plasma membrane, thus explaining the impaired growth factor signaling upon GOLPH3 depletion. Conversely, overexpression of GOLPH3, as observed in many tumor types, is sufficient to increase plasma membrane levels of growth factor receptors, promoting ligand-stimulated receptor activation, and propagating enhanced downstream signaling. Chapter 3 of the dissertation describes the role for GOLPH3 in establishing cell polarity and migration, which are key features of aggressive cancers. Both of the functions of GOLPH3 described in Chapters 2 and 3 require the ability for GOLPH3 to bind phosphatidylinositol-4-phosphate (PtdIns(4)P), a lipid uniquely enriched at trans-Golgi membranes, suggesting that it is the PtdIns(4)P/GOLPH3/MYO18A pathway at the Golgi which is responsible. This pathway, therefore, potentially contains novel targets for therapeutic intervention. Chapter 4 of the dissertation provides a summary and implications for future research.