The insulin-like growth factor 2 receptor (IGF2R) is a transmembrane glycoprotein with a complex structural architecture critical for its multifaceted biological roles. Structurally, IGF2R comprises seven extracellular domains organized into repeating β-sheets and α-helical motifs, facilitating ligand binding and intermolecular interactions. These extracellular regions are linked to a short transmembrane domain and a cytoplasmic tail containing tyrosine phosphorylation motifs that mediate intracellular signaling. Unlike typical growth factor receptors, IGF2R lacks intrinsic tyrosine kinase activity but recruits adaptor proteins like Grb2 and Shc to propagate downstream signals. Functionally, IGF2R serves dual roles as a clearance receptor for IGF2 and a transport regulator for lysosomal enzymes via mannose-6-phosphate (M6P) recognition. This dual functionality enables precise regulation of IGF2 bioavailability and proper lysosomal enzyme trafficking, crucial for normal cellular homeostasis. Emerging evidence highlights its tumor-suppressive properties through IGF2 sequestration and modulation of autophagy pathways. Furthermore, structural studies reveal conformational flexibility in its extracellular domains, allowing allosteric regulation during ligand binding and receptor internalization. Dysregulation of IGF2R has been implicated in developmental abnormalities and cancer progression, making it a potential therapeutic target for diseases characterized by IGF2 overexpression.
MET, also known as c-MET or HGFR (Hepatocyte growth factor receptor), is a transmembrane tyrosine kinase receptor that is encoded in humans by the MET gene. This receptor in charge of tyrosine-kinase activity is mapped at the chromosome 7q31.2 with 1408 amino acids. MET and its ligand HGF/SF (Hepatocyte growth factor/Scatter factor) are expressed in many tissues, principally in epithelial and mesenchymal origin cells, respectively. After binding to ligands, this tyrosine-protein kinase is rapidly internalized, polyubiquitinated and then degraded in a proteasome-dependent manner. MET is over-expressed in numerous types of neoplasms, such as tumors of the kidney, pancreas, thyroid and osteosarcoma. And it is reported that various mutations of MET gene are correlated with papillary renal carcinomas.