Met Activation and Receptor Dimerization in Cancer: A Role for the Sema Domain

Ligand dependent activity of receptor tyrosine kinases is critical for modulatingdownstream signaling and cell proliferation. In normal cellular context, hepatocytegrowth factor (HGF) regulates MET kinase activation and mediates cell proliferation,migration and motility. Recent elucidation of the MET extracellular domain suggests thatthe Sema domain, which bears structural similarity to other Semaphorins and Plexinfamily members, plays a critical role in ligand mediated receptor activation.Overexpression of MET which is observed in many cancers leads to ligand independentreceptor dimerization and activation. Evidence to support a role for the Sema domain incancer and therapeutic implications of targeting the Met Sema domain are discussed inthis review.