Understanding How the GOLPH3 Pathway Links the Golgi to Cancer

Juliati (Yuli) Rahajeng

Appointment Period: 2014-2016, Grant Years: [29,30]

Our laboratory has been focusing on the role of a Golgi peripheral membrane protein called GOLPH3 (GOLgi PHosphoprotein 3), an oncogene that is amplified and overexpressed in many different types of solid tumors. Its overexpression correlates with higher-grade tumors and worse prognoses for cancer patients. We previously showed that GOLPH3 regulates Golgi morphology and function through its interaction with PI4P (phosphatidylinositol-4-phosphate) and MYO18A, a myosin motor that works on Factin. We found that the PI4P/GOLPH3/ MYO18A/F-actin pathway is critical for creating a tensile force required for vesicle budding from the Golgi for transport to the plasma membrane.

Recently, we discovered that GOLPH3 is phosphorylated by DNA-PK after DNA damage (1, 2). GOLPH3 phosphorylation by DNA-PK enhances GOLPH3’s interaction with MYO18A and consequently results in dramatic Golgi vesiculation and dispersal following DNA damage. DNA-PK, GOLPH3, and MYO18A are all required for normal cell survival following DNA damage. Moreover, overexpression of GOLPH3 confers resistance to killing by DNA damage, an ability that likely contributes to GOLPH3’s role in conferring poor prognosis in cancer.

It is clear that GOLPH3’s function in vesicle exit from the Golgi underlies its ability to act as an oncogene. The mechanism of vesicle exit from the Golgi remains an important unsolved problem in biology. Therefore, we utilize several trafficking assays to study the mechanism by which GOLPH3 and its interactions with PI4P and MYO18A promote anterograde trafficking. 

PUBLICATIONS (resulting from this training)

Farber-Katz SE, Dippold HC, Buschman MD, Peterman MC, Xing M, Noakes CJ, Tat J, Ng MM, Rahajeng J, Cowan DM, Fuchs GJ, Zhou H, Field SJ. DNA damage triggers Golgi dispersal via DNA-PK and GOLPH3. Cell. 2014, 156(3):413-427.

Rahajeng J*, Buschman MD*, Field SJ. GOLPH3 links the Golgi, DNA damage, and cancer. Cancer Res. 2015, 75(4):624-7. Review.

*These authors gave equal contribution to the manuscript.