MET: A Critical Player in Tumorigenesis and Therapeutic Target

Abstract

Since its discovery more than 25 years ago, numerous studies have established that the MET receptor is unique among tyrosine kinases.Signaling through MET is necessary for normal development and for the progression of a wide range of human cancers.MET activation has been shown to drive numerous signaling pathways; however, it is not clear how MET signaling mediates diverse cellular responses such as motility, invasion, growth, and angiogenesis.Great strides have been made in understanding the pleotropic aspects of MET signaling using three-dimensional molecular structures, cell culture systems, human tumors, and animal models.These combined approaches have driven the development of MET-targeted therapeutics that have shown promising results in the clinic.Here we examine the unique features of MET and hepatocyte growth factor/scatter factor (HGF/SF) structure and signaling, mutational activation, genetic mouse models of MET and HGF/SF, and MET-targeted therapeutics.S ince the discovery of the receptor tyrosine kinase METand its ligand, hepatocyte growth factor/scatter factor (HGF/SF), numerous studies have established the significant role of this receptor/ligand pair in tumor growth and metastasis.The last 25 years of work has made it clear that MET is unique among receptor tyrosine kinases (RTKs), yet the MET receptor activates many signaling pathways that are common to other RTKs.Why MET activation produces growth in one cell type and invasion in another is still unclear, yet the variety of responses to MET signaling is what makes this receptor so frequently associated with malignant growth.Understanding the relationships between MET activation and its downstream signaling effectors is critical to the development of successful therapeutics for a wide range of malignancies.The MET oncogene was first identified in the early 1980s in a human osteosarcoma tumor cell line that was exposed to N-methyl-N 0 -nitro-N-nitrosoguanidine, which produced a chromosomal translocation and a novel fusion protein, between a region called the translocated promoter region (TPR) on chromosome 1 and MET kinase domain on chromosome 7.Here the activation of the MET tyrosine kinase domain occurs through the dimerization domain