Receptor tyrosine kinases (RTKs) are type-I membrane-bound proteins consisting of 58 members and can be further subdivided into 20 superfamilies [1]. RTKs function as receptors for various growth factors and transmit extracellular stimuli into cell nuclei through signal transduction [2]. Most cell surface RTKs share structural homology and are composed of an N-terminal extracellular binding domain, a single transmembrane domain, and a cytosolic C-terminal kinase domain [3]. In general, the N-terminal extracellular domain binds to its cognate ligand and then induces homo and/or heterodimerization of RTKs. After phosphorylation of the kinase domain at cytoplasmic tyrosine residues, RTKs provide docking sites for adaptor proteins and trigger signaling cascades [4]. Through the recruitment of various adaptors or effector proteins, a complex network of downstream pathways is activated, resulting in the activation of transcription factors involved in the regulation of cellular processes and biological functions.

However, the ability of RTKs to bridge the extracellular milieu and induce cellular responses is a double-edged sword. Aberrant expression of RTKs can be detected in various solid tumors and has been implicated in the invasion and metastatic progression of human cancer [5]. The activation of RTKs by mutations in the kinase domain of their intracellular signaling partners or cross-talk of RTKs can be demonstrated in a wide variety of human cancers [6]. Given their crucial role in carcinogenesis [7], RTKs and their signaling cascades are important therapeutic targets for human cancer [8]. Nevertheless, fundamental questions regarding the molecular basis of the involvement of RTKs in carcinogenesis remain unresolved, and most kinase inhibitors fail to cure cancer. Resistance to RTK inhibitors in solid tumors usually occurs within 1–2 years of starting therapy.

In sharp contrast to conventional RTK signaling, the unusual subcellular localization of RTKs[9], [10], especially membrane receptors in the nucleus (MRINs), was reported more than two decades ago [11]. A growing body of evidence indicates that at least 12 RTK families contain MRINs [12], [13], [14], [15], which exist in either full-length holoreceptor or truncated forms with novel functions [16]. Issues raised with these observations include the mechanism(s) underlying the nuclear translocation of RTKs and their functions in the nucleus during tumorigenesis. The current model of RTK trafficking from the cell surface into the nucleus suggests that this atypical phenomenon could occur in a ligand-dependent or ligand-independent manner [17]. Most importantly, the nuclear translocation of RTKs is significantly correlated with cancer development [18]. A well-known example is the presence of full-length epidermal growth factor receptor (EGFR, ErbB1) in the nucleus, which modulates cellular functions in human cancer and the response to cancer therapy [15], [19], [20].

RON (Receptuer d’Origine Nantatise, also known as macrophage stimulating 1 receptor, MST1R) has recently gained attention as a therapeutic target for human cancer. The structure, function, and conventional signal transduction of this protein have been extensively reviewed in recent articles [21], [22], [23]. Here, we summarize the biological roles of the cross-talk of RON with RTKs and membrane receptors, with a particular focus on the latest knowledge of the nuclear translocation of RON in human cancer [24], [25], [26]. This discussion will also incorporate recent progress, including the significance of nuclear RON in response to cellular stresses and alterations in biological function induced by nuclear RON.