Abstract
Inappropriate MET tyrosine kinase receptor signaling is detected in almost all types of human cancer and contributes to malignant growth and MET dependency via proliferative and antiapoptotic activities. Independently, Tensin-4 (TNS4) is emerging as a putative oncogene in many cancer types, but the mechanisms of TNS4 oncogenic activity are not well established. Here, we demonstrate that TNS4 directly interacts with phosphorylated MET via the TNS4 SH2-domain to positively regulate cell survival, proliferation, and migration, through increased MET protein stability. In addition, TNS4 interaction with β1-integrin cytoplasmic tail positively regulates β1-integrin stability. Loss of TNS4 or disruption of MET-TNS4 interaction triggers MET trafficking toward the lysosomal compartment that is associated with excessive degradation of MET and triggers MET-addicted carcinoma cell death in vitro and in vivo. Significant correlation between MET and TNS4 expression in human colon carcinoma and ovarian carcinoma suggests TNS4 plays a critical role in MET stability in cancer.