GOLPH3’s Role in Golgi Reorientation and Directional Trafficking in Cell Migration and GOLPH3-dependent Tumorigenesis
Golgi phosphoprotein 3 (GOLPH3) localizes to the trans-Golgi through specific binding to phosphotidylinositol-4-phosphate (PtdIns(4)P). GOLPH3 also binds to Myosin18A (MYO18A), linking the Golgi to the F-actin cytoskeleton. The GOLPH3 pathway is essential for normal Golgi morphology and efficient vesicular trafficking from the Golgi to the plasma membrane. Perturbation of the pathway results in changes to both Golgi morphology and secretory function, with functional consequences for the cell. Notably, GOLPH3 has recently been identified as the first example of an oncogene that functions at the Golgi. Overexpression of GOLPH3 has been associated with advanced malignancies in patients and implicated to enhance growth signaling and cell motility. However, the molecular mechanisms remain unclear. This dissertation presents studies on GOLPH3’s function in regulating cell migration as well as its role in different aspects of oncogenesis. Chapter 1 provides background information on the GOLPH3 pathway in the regulation of Golgi morphology and secretion. A review of GOLPH3-dependent pathologies of the Golgi and current understanding of GOLPH3’s involvement in cancer is provided. Chapter 2 describes in detail the mechanism by which the GOLPH3 pathway establishes directionality and regulates Golgi reorientation in cell migration. Chapter 3 describes studies of GOLPH3’s roles in protecting cells against DNA damage and regulating growth factor signaling, with implications to GOLPH3-dependnet tumorigenesis. On-going work on transgenic mouse models of GOLPH3 overexpression is also discussed. Finally, Chapter 4 concludes the findings of this dissertation and discusses future studies.