CMTM3 suppresses EGF-induced cell migration and STAT3 activation. CMTM3 downregulates EGFR expression via promoting EGFR degradation. CMTM3 interacts with Rab5. CMTM3 inhibits EGFR expression and EGF-mediated migration by enhancing Rab5 activity. C-terminal region of CMTM3 is more important in the tumor suppressive effects of CMTM3.