Dineli Wickramasinghe

Somatic Mutations Lead to an Oncogenic Deletion of Met in Lung Cancer

Activating mutations in receptor tyrosine kinases play a critical role in oncogenesis. Despite evidence that Met kinase is deregulated in human cancer, the role of activating mutations in cancers other than renal papillary carcinoma has not been well defined. Here we report the identification of somatic intronic mutations of Met kinase that lead to an alternatively spliced transcript in lung cancer, which encodes a deletion of the juxtamembrane domain resulting in the loss of Cbl E3-ligase binding. The mutant receptor exhibits decreased ubiquitination and delayed down-regulation correlating with elevated, distinct Met expression in primary tumors harboring the deleted receptor. As a consequence, phospho-Met and downstream mitogen-activated protein kinase activation is sustained on ligand stimulation. Cells expressing the Met deletion reveal enhanced ligand-mediated proliferation and significant in vivo tumor growth. A hepatocyte growth factor competitive Met antagonist inhibits receptor activation and proliferation in tumor cells harboring the Met deletion, suggesting the important role played by ligand-dependent Met activation and the potential for anticancer therapy. These results support a critical role for Met in lung cancer and somatic mutation-driven splicing of an oncogene that leads to a different mechanism for tyrosine kinase activation through altered receptor down-regulation in human cancer.

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.