FARP1 mediates cMET-driven motility in androgen-independent prostate cancer cells.

Activation of Rac1, a member of the Rho family of small GTPases and a well-established downstream effector of receptor tyrosine kinases (RTKs), has been linked to prostate cancer progression and predicts poor progression in prostate cancer patients. Rac1 and its upstream activators, the Rac guanine nucleotide exchange factors (Rac-GEFs), act as key drivers for RTK-mediated formation of actin-rich protrusions, structures involved in cancer cell motility and invasion. Our previous study identified VAV2 as the main Rac-GEF effector of epidermal growth factor receptor in androgen-independent cellular models. An unbiased RNAi screen targeting Rac-GEFs as effectors of cMET, which is an RTK frequently overexpressed in castration-resistant prostate cancer and associated with invasion and metastasis, identified the Rac-GEF FARP1 (FERM, ARH/RhoGEF and Plekstrin Domain Protein 1) as a pivotal contributor to Rac1-mediated migration and invasion. Notably, stimulation of cMET with its ligand Hepatocyte Growth Factor (HGF) promotes the formation of actin-rich protrusions through a PI3K-FARP1-Rac1-dependent pathway and independently of VAV2. Furthermore, FARP1 relocalizes to actin-rich protrusions in PC3 cells in response to HGF stimulation. Our results shed light on the distinctive contribution of Rac-GEFs to prostate cancer cell motility via RTKs and identify FARP1 as a crucial cMET-invasive effector. The differential coupling of RTKs to Rac-GEFs underscores the complexities of signaling events leading to Rac1 activation. It provides insight into the RTK effectors that contribute to prostate cancer cell invasiveness.