Disease relevance of MST1R

• We find activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer [1].
• Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus [1].
• In this report, we used an antibody phage display library to generate IMC-41A10, a human immunoglobulin G1 (IgG1) antibody that binds with high affinity (ED(50) = 0.15 nmol/L) to RON and effectively blocks interaction with its ligand, macrophage-stimulating protein (MSP; IC(50) = 2 nmol/L) [2].
• The RON and MET oncogenes are co-expressed in human ovarian carcinomas and cooperate in activating invasiveness [3].
• In a human gastric cancer cell line (KATO-III), we found abnormal accumulation of an uncleaved single-chain protein (delta-Ron) of 165 kDa; this molecule is encoded by a transcript differing from the full-length RON mRNA by an in-frame deletion of 49 amino acids in the beta-chain extracellular domain [4].
• Although stimulation with HGFL had no effect on proliferation, concurrent RON receptor blockade and gemcitabine treatment increased apoptosis of RON-expressing pancreatic cancer cells versus gemcitabine treatment alone [5].

Psychiatry related information on MST1R

• Each of them resulted in prolonged reaction times (RT) in the duration discrimination task and elicited the MMN, P3a, and RON components of the ERP [6].

High impact information on MST1R

• MSP bound to RON on normal human bronchial epithelial cells with a high affinity (Kd = 0.5 nM) and induced autophosphorylation of RON [7].
• Here we show that in contrast to the HGF receptor, which was expressed at the basolateral surface, RON was localized at the apical surface of ciliated epithelia in the airways and oviduct [7].
• Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility [7].
• RON, a cDNA homologous to the hepatocyte growth factor (HGF) receptor gene (MET), encodes a putative tyrosine kinase [8].
• Here we show that the RON gene is expressed in several epithelial tissues as well as in granulocytes and monocytes [8].

Biological context of MST1R

• RON is a receptor tyrosine kinase of the MET family that is involved in cell proliferation, cell survival, and cell motility in both normal and disease states [9].
• Thus, occupancy of the RON receptor by MSP activates distinct signal transduction pathways that mediate several cellular responses [10].
• A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype [4].
• The proto-oncogene, c-Cbl, which modulates ubiquitylation of RON, was increased in glia in both MS brains and EAE spinal cords [11].
• RON-regulated innate immunity is protective in an animal model of multiple sclerosis [11].

Anatomical context of MST1R

• The MSP-RON signaling pathway has been implicated in the functional regulation of mononuclear phagocytes [7].
• Another major contribution of this report is an extensive analysis of RON expression in approximately 100 cancer cell lines and approximately 300 patient tumor samples representing 10 major cancer types [2].
• The MSP receptor regulates alpha6beta4 and alpha3beta1 integrins via 14-3-3 proteins in keratinocyte migration [12].
• Immunohistochemistry revealed that RON was expressed in germinal centers of tonsil, in skin, small intestine, and colon [13].
• These data suggest that RON initiates signaling pathways that negatively regulate HIV-1 transcription in monocytes/macrophages and that HIV-1 suppresses RON function by decreasing protein levels in the brain to assure efficient replication [14].

Associations of MST1R with chemical compounds

• Increased expression of RON and its variants resulted in colony formation and motile activities of colonic epithelial AA/C1 cells as evident in soft-agar and migration assays, respectively [15].
• Here we present a crystal structure of the 30 kDa beta-chain of human HGFl/MSP, a serine proteinase homology domain containing the high-affinity binding site for the RON receptor [16].
• We investigated the pathway involved in integrin-mediated RTK activation, using RON, the receptor for macrophage-stimulating protein [17].
• Further, we show that activated RON inhibited the iNOS gene transcription activity as assessed by chloramphenicol acetyltransferase activity in Raw264.7 cells expressing RON [18].
• Treatment of MDA MB 231 cells with mithramycin A, an inhibitor of Sp1 binding, or siRNA knock-down of Sp1 blocked RON gene expression and MSP-mediated invasion of MDA MB 231 cells [19].

Physical interactions of MST1R

• Moreover, phosphorylated RON formed a complex with PI-3 kinase in both HK-NOC keratinocyte and RON cDNA-transfected MDCK cells [20].

Regulatory relationships of MST1R

• HK2 produced MSP and expressed RON in a form that was phosphorylated by rMSP [21].
• To determine the oncogenic potential of RON, transgenic mice were generated using the surfactant protein C promoter to express human wild-type RON in the distal lung epithelial cells [22].
• One of the mechanisms of JSRV-induced cell transformation that has been proposed for epithelial cells involves JSRV Env binding Hyaluronidase 2 (the JSRV receptor), thereby inducing its degradation and allowing the release and activation of RON tyrosine kinase which is normally suppressed by HYAL-2 [23].

Other interactions of MST1R

• Our findings suggest that the MSP-RON signaling pathway is a novel regulatory system of mucociliary function and might be involved in the host defense and fertilization [7].
• The RON and SEA genes encode tyrosine kinases that are structurally homologous to the HGF receptor [24].
• The MSP receptor is a transmembrane protein tyrosine kinase [25].
• RON expression is also essential for TGF-beta1-induced expression of alpha-smooth muscle actin (alpha-SMA), a specialized mesenchymal marker [26].
• In addition to activation and phosphorylation of RON, MSP also induced tyrosine phosphorylation of the PI-3 kinase p85 subunit in a time-dependent manner, with a peak at 15 min [20].

Analytical, diagnostic and therapeutic context of MST1R

• The expression of the MSP receptor, RON, was evaluated in HMC and HK2 by Western blot [21].
• RON mRNA was investigated in HMC by RT-PCR [21].
• The expression of MSP and RON in normal human renal tissue was studied by immunohistochemistry [21].
• Specific immunoprecipitation with ID-1 and ID-2 or anti-MET antibody followed by Western blotting under reducing conditions with rabbit polyclonal antibodies against RON and MET showed that our anti-RON antibodies recognize specifically the RON receptor [13].
• We analyzed the expression of RON receptor in a number of human hematopoietic and nonhematopoietic cells lines by flow cytometry [13].

References