J. Clin. Invest. 109: 863–867 (2002). DOI: 10.1172/JCI200215418. enzyme capable of processing pro-HGF to produce HGF. A number of serine-like proteases, including urokinase-type plasminogen activator and coagulation factor XII, have such an activity and have been detected in some tumors. Nevertheless, the mechanism by which pro-HGF is converted to HGF in tumor tissues remains to be established. Ligand-independent mechanisms. Met can also be activated in an HGF-independent manner in tumors, particularly as a result of Met overexpression, which occurs in almost every case of differentiated papillary carcinomas. Increased Met expression can be mediated by MET gene amplification, by enhanced transcription, or by posttranscriptional mechanisms. Increased expression of Met on the cell surface apparently favors ligandindependent activation through spontaneous Met dimerization, but it is not generally sufficient to trigger Met activation. In some cases, even very high expression of Met does not cause constitutive receptor activation (11). Noncovalently associated, inactive clusters of these receptors have been identified on the cell surface, perhaps explaining the cells’ resistance to transformation, even in the face of high Met levels (12). An additional signal, such as Met transactivation by other membrane receptors, may be required to activate signaling by these receptors. Alternatively, these clusters may contain suppressor molecules that prevent spontaneous Met activation in normal cells but may be lost or inactivated in tumor cells. One well-known oncogenic form of Met, first identified in the chemically transformed human osteosarcoma cell line HOS (1), is the product of the TPR-MET fusion, which arises through a chromosomal rearrangement. The resulting chimeric gene contains the promoter and the N-terminal sequence of the TPR gene from chromosome 1, fused with the C-terminal sequence of MET, which maps to chromosome 7. The TPR-MET chimeric gene encodes a cytoplasmic protein with molecular weight 65 kDa comprising the TPR leucine zipper domain and the Met kinase domain. This protein is constitutively active as a result of TPR leucine zipper interactions, which allow for Met kinase dimerization, transphosphorylation, and activation (13), and it is potently oncogenic in vitro and in vivo. Abnormal processing or the absence of normal negative regulators can also lead to constitutive Met activation and tumorigenesis. The mature Met consists of two subunits, α and β, arising from proteolytic cleavage of the single-chain precursor. As a result of defective posttranslational processing, the precursor fails to be cleaved in the colon carcinoma cell line LoVo; consequently, Met is expressed on the cell surface as a single-chain molecule, which is constitutively tyrosinephosphorylated (14). In metastatic B16 melanoma cells, on the other hand, cytosolic phosphatases that normally mediate Met dephosphorylation, internalization, and degradation are downregulated, leading to constitutive Met activation (15). Finally, a large class of somatic or inherited mutations in the MET gene can lead to active, typically ligand-independent, Met signaling in tumor cells. For instance, a mutant in which the Met cytoplasmic domain is truncated immediately below the trans-