Gallo Simona, Folco Consolata Beatrice, Crepaldi Tiziana
Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy.
Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy.
Int J Mol Sci. 2024 Dec 21;25(24):13692. doi: 10.3390/ijms252413692.
The MET oncogene, encoding the hepatocyte growth factor (HGF) receptor, plays a key role in tumorigenesis, invasion, and resistance to therapy, yet its full biological functions and activation mechanisms remain incompletely understood. A feature of MET is its extensive interaction network, encompassing the following: (i) receptor tyrosine kinases (RTKs); (ii) co-receptors (e.g., CDCP1, Neuropilin1); (iii) adhesion molecules (e.g., integrins, tetraspanins); (iv) proteases (e.g., ADAM10); and (v) other receptors (e.g., CD44, plexins, GPCRs, and NMDAR). These interactions dynamically modulate MET's activation, signaling, intracellular trafficking, and degradation, enhancing its functional versatility and oncogenic potential. This review offers current knowledge on MET's partnerships, focusing on their functional impact on signaling output, therapeutic resistance, and cellular behavior. Finally, we evaluate emerging combination therapies targeting MET and its interactors, highlighting their potential to overcome resistance and improve clinical outcomes. By exploring the complex interplay within the MET network of interacting cell surface proteins, this review provides insights into advancing anti-cancer strategies and understanding the broader implications of RTK crosstalk in oncology.
MET癌基因编码肝细胞生长因子（HGF）受体，在肿瘤发生、侵袭和治疗耐药性中起关键作用，但其完整的生物学功能和激活机制仍未完全明确。MET的一个特点是其广泛的相互作用网络，包括以下方面：（i）受体酪氨酸激酶（RTK）；（ii）共受体（如CDCP1、神经纤毛蛋白1）；（iii）黏附分子（如整合素、四跨膜蛋白）；（iv）蛋白酶（如ADAM10）；以及（v）其他受体（如CD44、丛状蛋白、G蛋白偶联受体和N-甲基-D-天冬氨酸受体）。这些相互作用动态调节MET的激活、信号传导、细胞内运输和降解，增强其功能多样性和致癌潜力。本综述提供了关于MET伙伴关系的当前知识，重点关注它们对信号输出、治疗耐药性和细胞行为的功能影响。最后，我们评估了针对MET及其相互作用分子的新兴联合疗法，强调了它们克服耐药性和改善临床结果的潜力。通过探索相互作用的细胞表面蛋白的MET网络内的复杂相互作用，本综述为推进抗癌策略和理解RTK串扰在肿瘤学中的更广泛意义提供了见解。
