Met-related receptor tyrosine kinase Ron in tumor growth and metastasis

Abstract

The Ron receptor is a member of the Met family of cell surface receptor tyrosine kinases and is primarily expressed on epithelial cells and macrophages. The biological response of Ron is mediated by binding of its ligand, hepatocyte growth factor-like protein/macrophage stimulating-protein (HGFL). HGFL is primarily synthesized and secreted from hepatocytes as an inactive precursor and is activated at the cell surface. Binding of HGFL to Ron activates Ron and leads to the induction of a variety of intracellular signaling cascades that leads to cellular growth, motility and invasion. Recent studies have documented Ron overexpression in a variety of human cancers including breast, colon, liver, pancreas, and bladder. Moreover, clinical studies have also shown that Ron overexpression is associated with both worse patient outcomes as well as metastasis. Forced overexpression of Ron in transgenic mice leads to tumorigenesis in both the lung and the mammary gland and is associated with metastatic dissemination. While Ron overexpression appears to be a hallmark of many human cancers, the mechanisms by which Ron induces tumorigenesis and metastasis are still unclear. Several strategies are currently being undertaken to inhibit Ron as a potential therapeutic target; current strategies include the use of Ron blocking proteins, small interfering RNA (siRNA), monoclonal antibodies, and small molecule inhibitors. In total, these data suggest that Ron is a critical factor in tumorigenesis and that inhibition of this protein, alone or in combination with current therapies, may prove beneficial in the treatment of cancer patients.

Figure 1

The Ron and Met receptor tyrosine kinases exhibit important similarities and differences between receptors. Structurally, Ron and Met are similar in that both receptors are single-pass, disulfide linked α/β heterodimers. However, the amino acid identity between Ron and Met is not high (34% overall) but the intracellular region involved in signal transduction is conserved (63%). The ligands for Ron and Met, HGFL and HGF respectively, also share a similar structure and have an overall amino acid identity of 45%. In contrast to their structural similarity, HGFL and HGF are secreted ligands, which originate from different cell types, with HGFL produced as an endocrine molecule secreted primarily from hepatocytes and HGF produced from meschemycal cells operating in a paracrine fashion. Binding of HGFL or HGF to their corresponding receptor induces receptor dimerization and trans-autophosphorylation of tyrosine residues (1238/1239 Ron and 1234/1235 Met) in the tyrosine kinase domain, leading to the tyrosine phosphorylation of key C-terminal residues (1353/1360 Ron and 1349/1356 Met). Activation of either receptor results in recruitment of several downstream adaptor molecules and initiation of robust signaling responses. Signaling pathways that are impacted by these receptors include the PI3-K, Akt, β-catenin, Ras, MAPK and JAK/STAT pathways which induce pleiotropic biologic events such as proliferation, migration, invasion, cell scattering and branching morphogenesis.