Ron receptor tyrosine kinase signaling as a therapeutic target

Abstract

Introduction: Since its discovery nearly 20 years ago, the Ron receptor tyrosine kinase has been extensively studied. These studies have elucidated many of the major signaling pathways activated by Ron. In the context of the inflammation and cancer, studies have shown that Ron plays differential roles; Ron activation limits the inflammatory response, whereas in cancer, Ron activation is associated with increased metastases and poor prognosis.

Areas covered: This review discusses the current literature with regard to Ron signaling and consequences of its activation in cancer as well as its role in cancer therapy. Further, we discuss the mechanisms by which Ron influences the inflammatory response and its role in chronic inflammatory diseases. Finally, we discuss Ron's connection between chronic inflammation and progression to cancer.

Expert opinion: The complex nature of Ron's signaling paradigm necessitates additional studies to understand the pathways by which Ron is functioning and how these differ in inflammation and cancer. This will be vital to understanding the impact that Ron signaling has in disease states. Additional studies of targeted therapies, either alone or in conjunction with current therapies are needed to determine if inhibition of Ron signaling will provide long-term benefits to cancer patients.

Figure 1. Schematic of the known signaling partners of Ron

A) HGFL dependent and independent Ron signaling. HGFL dependent Ron signaling impacts a variety of cell functions and induces multiple downstream effector pathways, including FAK [82] and JNK [83, 84], in which we have little information on the signaling intermediates. Activation of NF-κB is facilitated by IκB phosphorylation and dissociation, leading to chemokine production [46]. Activation of VEGF is mediated MAPK [47] via SRC [85]. PI3K activates AKT signaling with increased survival as one consequence [82]. Additionally, Ron was found to facilitate plectin/integrin B-4 (ITGB4) via PI3K phosphorylation of ITGB4 in a cyclic fashion, which is proposed as a mechanism by which migration occurs [51]. The best-characterized signaling cascade is activation of Erk. Ron signals through son of sevenless (SOS) and Ras [86], which activate RAF and MEK [54], leading to activation of Erk. Erk activation can activate multiple pathways, including the phosphorylation and nuclear translocation of RSK, which leads to EMT [39]. Alternatively, Erk phosphorylates β-catenin, leading to nuclear translocation and increases in c-myc and cyclin D expression [44]. For HGFL independent activation, Ron activates FAK and leads to increased cell spreading and survival [29]. B) Truncated versions of Ron (murine mRon, Δ165 [33] and 165.e11p [38]) are constitutively phosphorylated within the cytoplasm, which leads to activation of the AKT and Erk1/2 pathways and an EMT phenotypic change [38]. C) Ron can form heterodimers with other tyrosine kinases. Recent work demonstrated that Ron form heterodimers with IGF1R. Stimulation of IGF1R by ligand leads to phosphorylation of both receptors, IGF1R mediated activation of Stat3 and increased migration; however, HGFL binding of Ron is unable to activate this signaling cascade [30]. This unidirectional signaling is unique to the Ron:IGF1R heterodimer, whereas receptor binding to either Ron or EGFR can lead to phosphorylation of Ron:EGFR heterodimers and induce migration [31].