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首页> 外文期刊>Developmental cell >Tensin-4-dependent MET stabilization is essential for survival and proliferation in carcinoma cells
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Tensin-4-dependent MET stabilization is essential for survival and proliferation in carcinoma cells

机译：依赖Tensin-4的MET稳定对于癌细胞的存活和增殖至关重要

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摘要

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 antiapoptoticactivities. 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 interactiontriggers MET trafficking toward the lysosomal compartment that is associated with excessive degradation of MET and triggers MET-addicted carcinoma cell death invitro and invivo. 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.
机译：在几乎所有类型的人类癌症中都检测到不合适的MET酪氨酸激酶受体信号传导，并通过增殖和抗凋亡活性促进恶性生长和MET依赖性。独立地，Tensin-4（TNS4）在许多癌症类型中均作为推定的致癌基因出现，但TNS4致癌活性的机制尚不十分清楚。在这里，我们证明TNS4通过TNS4 SH2-结构域与磷酸化的MET直接相互作用，以通过增加MET蛋白质的稳定性来积极调节细胞的存活，增殖和迁移。此外，TNS4与β1-整合素细胞质尾部的相互作用正调控β1-整合素的稳定性。 TNS4的丧失或MET-TNS4相互作用的破坏触发了MET向溶酶体区室的运输，这与MET的过度降解有关，并触发了MET上瘾的癌细胞的体外和体内死亡。 MET和TNS4在人结肠癌和卵巢癌中的表达之间存在显着相关性，表明TNS4在癌的MET稳定性中起关键作用。

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