Abstract
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.