Disease relevance of Mst1r

• Previous studies have shown that mice deficient in the tyrosine kinase domain (TK-/-) of the receptor Mst1r have an increased susceptibility to nickel (Ni)-induced acute lung injury (ALI) [1].
• Genes responsible for inflammation, edema, and lymphocyte function were altered in the Mst1r TK-/- mice [1].
• This observation, coupled with earlier work, suggested that Sf-Stk drives the expansion of infected cells by forming a complex with the Friend virus envelope glycoprotein, gp55, and the erythropoietin receptor [2].
• The Friend virus susceptibility gene 2 (Fv2) controls the polyclonal expansion of infected cells that occurs early during Friend erythroleukemia virus infection [2].
• Thus, with regard to this particular Fv-2 phenotype (susceptibility to FV-P-induced cellular hyperplasia), Fv-2 manifests itself specifically in the erythroid lineage, either in mature (d3) BFU-E or CFU-E [3].

High impact information on Mst1r

• Fv2 encodes a truncated form of the Stk receptor tyrosine kinase [4].
• We mapped Fv2 to a 1.0-Mb interval that also contained the gene (Ron) encoding the stem cell kinase receptor (Stk) [4].
• The Fv-2 genotype of erythroid progenitors directly determines whether they will undergo viral-induced transformation [3].
• We suggest that the observed skewing in composition among the various mature blood cell types in C57BL/6 in equilibrium DBA/2 allophenic mice is caused by allelic variants of the Stk gene [5].
• For the effect on the S phase fraction of CFU-S, we refer to the gene(s) as Stk (stem cell kinetics) [5].

Chemical compound and disease context of Mst1r

• Friend spleen focus-forming virus transforms rodent fibroblasts in cooperation with a short form of the receptor tyrosine kinase Stk [6].
• Using a well-characterized model of LPS-induced acute liver failure (ALF) in galactosamine (GalN)-sensitized mice, we show that Ron TK(-/-) mice display marked protection compared with control Ron TK(+/+) mice [7].

Biological context of Mst1r

• Gene expression profiles of Mst1r-deficient mice during nickel-induced acute lung injury [1].
• Construction of a D2.B6-Fv-2r congenic mouse strain: nonlethality of the homozygous Fv-2' genotype [8].
• A naturally occurring point substitution in Cdc25A, and not Fv2/Stk, is associated with altered cell-cycle status of early erythroid progenitor cells [2].
• The gene Rv-2, which controls susceptibility to spleen focus formation, was assigned to chromosome 9, and closely linked to the Fv-2 gene, by using the two congenic strains B10.C(47N)/Sn and B6.C-H-7b/By [9].
• The allelic difference of Fv-2 had no significant effect on the proportion of other progenitor or stem cells (CFU-E, CFU-C or CFU-S) normally undergoing DNA synthesis in the hemopoietic tissues, or on the hemoglobin concentration, red blood cells, hematocrit, total of differential white blood cell counts in the peripheral blood of these animals [10].

Anatomical context of Mst1r

• In addition, the Mst1r TK-/- lungs showed clusters of cells near the vascular endothelium and airways [1].
• These results suggest that Mst1r signaling may be involved in the regulation of macrophage and T-lymphocyte activation in vivo during injury [1].
• Mouse strains that are homozygous for the resistant allele of Fv2 (Fv2(rr)) have few actively cycling BFU-Es [2].
• Activation of the stem cell-derived tyrosine kinase/RON receptor tyrosine kinase by macrophage-stimulating protein results in the induction of arginase activity in murine peritoneal macrophages [11].
• The Ron/STK receptor tyrosine kinase is a member of the c-Met family of receptors and is activated by hepatocyte growth factor-like protein (HGFL) [12].

Associations of Mst1r with chemical compounds

• To examine the role of Mst1r in ALI in more detail, we compared the gene expression profiles of murine lung mRNA from control and Mst1r TK-/- mice at baseline and after 24 h of particulate Ni sulfate exposure [1].
• Fv2 has recently been shown to encode a truncated form of the Stk receptor tyrosine kinase (Sf-Stk) [2].
• The scatter response of the 293-Ron cells was also attenuated by treatment of the cells with the specific EGFR inhibitor AG 1478 [13].
• These results indicate that both gp55 and Epo stimulate EpoR and that the Fv-2 gene encodes a protein that controls response to these ligands [14].
• The targeted deletion of the cytoplasmic domain of the Ron receptor tyrosine kinase (TK) in mice leads to exaggerated responses to injury in several murine models of inflammation as well as increased lethality in response to endotoxin (lipopolysaccharide [LPS]) [7].

Regulatory relationships of Mst1r

• Fv2 has also been implicated in the control of cell cycling in early erythroid progenitors (erythroid blast-forming units [BFU-Es]) [2].
• In addition, we show that the Kit+ pathogenic targets of Friend virus in the spleen are distinct from the pathogenic targets in bone marrow and this population of spleen target cells is markedly decreased in W/W(v) mice and these cells fail to express Sf-Stk [15].
• We report that Ron mRNA is expressed by NGF-dependent sensory and sympathetic neurons and that these neurons survive and grow with MSP at different stages of development [16].

Other interactions of Mst1r

• The observed recombination frequency for the intervals between Fv-2 and Bgl-s was 6.8% [8].
• Cross-talk between the receptor tyrosine kinases Ron and epidermal growth factor receptor [13].
• This transformation by SFFV gp55 requires the kinase activity of sf-Stk and the presence of its extracellular domain but not expression of the EpoR or the tyrosine kinase Jak2, which is required for activation of signal transduction pathways through the EpoR [6].
• Macrophage-stimulating protein, the ligand for the stem cell-derived tyrosine kinase/RON receptor tyrosine kinase, inhibits IL-12 production by primary peritoneal macrophages stimulated with IFN-gamma and lipopolysaccharide [17].
• Cross-linking experiments show that non-covalent Met-Ron complexes are present on the cell surface, before ligand-induced dimerization [18].
• We demonstrate that Stat3 is required for the Epo-independent growth of Friend virus-infected cells and that the activation of Stat3 by Sf-Stk is mediated by a novel Stat3 binding site in Gab2 [19].

Analytical, diagnostic and therapeutic context of Mst1r

• In situ hybridization analysis demonstrates that Ron is expressed in the trophectoderm at embryonic day (E) 3.5 and is maintained in extraembryonic tissue through E7.5, compatible with an essential function at this stage of development [12].
• STK was assigned by fluorescent in situ hybridization to the R-positive F1 band of chromosome 9, the same region to which hepatic growth factor-like protein has been assigned [20].
• Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells [20].
• Transphosphorylation is direct, as it occurs in Met or Ron receptors lacking the docking sites for signal transducers [18].
• On the other hand, RT-PCR analysis showed that STK/RON mRNA was expressed in sperm collected from both testis and epididymis [21].

References