The Ron receptor tyrosine kinase (RTK) has been implicated in the progression of a number of carcinomas, thus understanding the regulatory mechanisms governing its activity is of potential therapeutic significance. A critical role for thejuxtamembrane domain in regulating RTK activity is emerging, however the mechanism by which this regulation occurs varies considerably from receptor to receptor.
Unlike other RTKs described to date, tyrosines in the juxtamembrane domain of Ron are inconsequential for receptoractivation. Rather, we have identified an acidic region in the juxtamembrane domain of Ron that plays a central role in promoting receptor autoinhibition. Furthermore, our studies demonstrate that phosphorylation of Y1198 in the kinasedomain promotes Ron activation, likely by relieving the inhibitory constraints imposed by the juxtamembrane domain.
Taken together, our experimental data and molecular modeling provide a better understanding of the mechanisms governing Ron activation, which will lay the groundwork for the development of novel therapeutic approaches for targetingRon in human malignancies.
Conserved surface residues and surface potential of the Ron kinase domain (3PLS). The conserved region adjacent to the active site with a predominantly positive surface potential is indicated by arrows as the putative JM-C binding site. A)Conserved residues on the surface of human kinase domains are indicated, with red/orange representing highly conserved residues and blue/cyan representing highly variable residues. B) Surface potential of the Ron kinase domain, with blue representing positive potential and red representing negative potential. The units of the scale were −60.362~60.362.