Oncotarget. these inhibitors for combined therapy. gene but not the gene was amplified. Experimentally, c-Met is shown to have stronger kinase activity than RON  and thus it is possible that c-Met may be more efficient at activating RON than RON-RON homodimers. The requirement of RON for oncogenic addiction to c-Met implies that c-Met-RON heterodimers promote different signaling cascades because of diverse platforms. However, c-Met and RON possess remarkably similar tyrosine binding sites that serves as docking sites for adaptor or signaling molecules and thus the signaling platforms may be redundant. This appears to not be the case given their differences in strengths as kinases and the recent finding that Grb2 binds directly and is responsible for the biologic activity of c-Met; whereas, RON relies chiefly on Gab1; whereas, Gab2 binding to RON attenuates Gab1 recruitment and represses signaling . 4-Aminophenol As is the case with heterodimers from the EGFR family of receptors, signaling from heterodimers creates signaling diversity. Thus, depending on the relative abundance of each receptor type RON expression may in part modulate c-Met activity and vice versa. In this context, we recently showed that knockdown of RON enhanced the level and duration of HGF mediated activation of MAPK and AKT . The functional relevance of c-Met-RON heterodimers has not been fully investigated. However, two separate studies suggest that genetic knock down of RON leads to up regulation on c-Met signaling [44, 46]. Thus, separately inhibiting either of these receptor kinases may lead to compensation by the other. Studies also indicate that c-Met and RON may interact with other phosphotyrosine kinases. Lowy and his colleagues recently showed that MSP stimulated RON was unable to activate 4-Aminophenol IGF1-R but that IGF1 or EGF treatment caused phosphorylation of RON [47, 48]. Thus IGF1-R activation of Ron was unidirectional. In contrast, MSP was able to phosphorylate both c-Met and EGFR in a RON dependent manner and activated RON was co-immunoprecipitated with each of these receptors [47, 48]. Similarly c-Met is known to activate IGF1-R . However, activation of c-Met or RON by IGF or EGF is relatively weak and the significance of this is yet to be firmly established. A separate study showed that activated EGFR is able to phosphorylate c-Met indirectly through Src . Regardless of the mechanisms, c-Met and RON are likely to modulate signaling by direct or indirect interaction with other phosphotyrosine kinase receptors. Pathways activated and biologic consequence of c-Met and Ron activation The recruitment and binding of substrates/adaptor proteins to the phosphorylated carboxy-terminal docking sites of activated c-Met and RON provides the platform to activate signaling cascades. As described above, the docking sites are Tyr-1349 and Tyr-1356 for c-Met and Tyr-1353 and Tyr-1360 for RON. Potential signaling cascades are illustrated in Figure ?Figure22 and most appear dependent on PI3K and MAPK activation as central switches. Major signaling molecules activated through c-Met and RON signaling include MAPK, PI3K/AKT, c-Src, STAT3, NF-B, FAK and -catenin and most of these may be dependent on PI3K and MAPK. The mediators of c-Src and STAT3 by c-Met and RON are not fully determined although JAK inhibitors blocked STAT3 activation by HGF stimulation in some cell lines suggesting that JAK could interact directly or indirectly with c-Met. These activated signaling molecules in turn govern the cellular responses to activated c-Met or RON. Open in a separate window Figure 2 An illustration representing interaction of c-Met or RON with other cell surface receptorsHomodimerization of c-Met or RON appears preferable although c-Met and RON can form heterodimers leading to transphosphorylation. c-Met and RON may interact with and transphosphorylate other receptor tyrosine kinases including members of MAPKAP1 the EGFR family. A separate type of interaction for c-Met is with CD44, a non-kinase transmembrane receptor. Isoforms of CD44 bind and apparently sequester HGF at the membrane, acting a co-receptor 4-Aminophenol for presentation of ligand to c-Met. Numerous cellular responses are attributed to c-Met and RON signaling and these induce but are not limited to cytoskeletal changes, EMT, migration and invasion, stemness, resistance to apoptosis, angiogenesis and proliferation. It is likely that activation of down stream molecular targets and subsequent.