THE MECHANISM OF PRL-3 SIGNALLING UNDER CELLULAR STRESS

Abstract

PRL-3 IS KNOWN TO EXHIBIT PLEIOTROPIC EFFECTS IN CANCER PROGRESSION, INCLUDING PROMOTING CELL PROLIFERATION, SUSTAINING CELL SURVIVAL, INDUCING ANGIOGENESIS, AND ENHANCING INVASION AND METASTASIS. HOWEVER, THE SIGNALLING MECHANISMS OF PRL-3 REMAIN LARGELY UNKNOWN. HERE, PRL-3 WAS IDENTIFIED AS A NOVEL ACTIVATOR OF MTORC1. PRL-3 INDUCED AN ABERRANT ACTIVATION OF MTOR SIGNALLING IN CANCER CELLS BY USING A TWO-PRONGED APPROACH: 1) INCREASING RHEB-GTP ACCUMULATION VIA ACTIVATION OF AKT-TSC2 SIGNALLING, AND 2) ENHANCING RAG GTPASES-MEDIATED MTORC1 RECRUITMENT TO LYSOSOMES FOR RHEB-MEDIATED ACTIVATION. THIS PRL-3-MEDIATED ACTIVATION OF MTORC1 RESULTED IN INCREASED CELL MOTILITY, INVASIVENESS, AND MMP-2/9 PRODUCTION. MOREOVER, A PROTECTIVE EFFECT OF PRL-3 AGAINST COCL2-INDUCED APOPTOSIS WAS REPORTED. THIS WAS P38 MAPK-DEPENDENT AND MECHANISTICALLY INVOLVED DEPHOSPHORYLATION OF THE PRO-APOPTOTIC KINASE. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF PRL-3 SIGNALLING AND HIGHLIGHT POTENTIAL