Oncogenic receptor tyrosine kinase signaling is driven by the Golgi protein GOLPH3 and its interaction with MYO18A.

Receptor tyrosine kinase (RTK) signaling drives cancer and is a validated therapeutic target. Modulators of RTK signaling can reveal mechanisms of oncogenesis and offer new therapeutic targets. Golgi phosphoprotein 3 (GOLPH3) is a Golgi-localized oncoprotein that promotes signaling downstream of mTOR. Here, examination of RTK signaling indicated that GOLPH3 acted at the level of the RTK and increased all downstream signaling. We found that GOLPH3 enhanced the delivery of RTKs to the plasma membrane. This role was shared with its binding partner myosin 18A (MYO18A) and depended on the interaction of GOLPH3 with MYO18A. The GOLPH3-MYO18A complex at the Golgi apparatus was required and rate-limiting for RTK signaling across the cell types and receptors assessed. Our findings provide insight into the relationship between the function of GOLPH3 at the Golgi and its role as a cancer driver, highlighting its potential as a therapeutic target in cancer.