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Gene Review

MST1  -  macrophage stimulating 1 (hepatocyte...

Homo sapiens

Synonyms: D3F15S2, DNF15S2, HGFL, Hepatocyte growth factor-like protein, MSP, ...
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Disease relevance of MST1

  • 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) [1].
  • A human hepatoma (HepG2) cell line library was screened with an oligonucleotide probe for macrophage stimulating protein (MSP) to clone an MSP cDNA [2].
  • The DNF15S2 locus has been proposed to code for one or more tumor suppressor genes since this locus is deleted in DNA from small cell lung carcinoma, other lung cancers, renal cell carcinoma, and von Hippel-Lindau syndrome [3].
  • MSP mRNA expression in endometrial epithelial cells was significantly up-regulated in endometriosis patients during the late secretory phase compared with expression in controls [4].
  • Nitrosamine-treated hamsters also demonstrate pulmonary neuroendocrine cell apoptosis in situ during the same time period as expression of the endogenous HGFL/ MSP gene, immediately preceding the spontaneous regression of neuroendocrine cell hyperplasia [5].

Psychiatry related information on MST1

  • A comparison of speech perception of cochlear implantees using the Spectral Maxima Sound Processor (SMSP) and the MSP (MULTIPEAK) processor [6].
  • The unidimensionality and cumulativeness of the subscales Health Perceptions, Mental Health, Physical Pain, and Social Functioning of the MOS Short-form General Health Survey were investigated using the Mokken Scale Analysis for Polychotomous Items (MSP) [7].

High impact information on MST1


Chemical compound and disease context of MST1

  • We wished to test the hypothesis that MSP and its tyrosine kinase receptor, RON, might represent an autocrine/paracrine system involved in the pathogenesis of human nonneuroendocrine lung tumors, the non-small-cell carcinomas (NSCLCs) [11].
  • Mefloquine is the treatment of choice for uncomplicated multiresistant falciparum malaria, and in combination with sulphadoxine and pyrimethamine (MSP) at a single dose of 15/30/1.5 mg/kg, respectively, has been used in Thailand for the past 6 years [12].
  • Bisulfite-modified DNA sequencing and MSP assay showed aberrant methylation of TIMP-2 5'-CpG island in 17 of 36 (47%) invasive cervical carcinomas and in 2 of 3 cervical cancer cell lines [13].
  • Previous experiments have shown that a Synechocystis sp. PCC 6803 mutant (delta psbO) lacking the extrinsic manganese-stabilizing protein (MSP) exhibits impaired, but significant levels of H2O-splitting activity [Burnap, R., & Sherman, L.A. (1991) Biochemistry 30, 440-446] [14].
  • To this end, we undertook a comparative controlled trial of the new triple combination, mefloquine-sulphadoxine-pyrimethamine (MSP, Fansimef) with chloroquine in a group of Nigerian children with symptomatic falciparum malaria [15].

Biological context of MST1


Anatomical context of MST1


Associations of MST1 with chemical compounds


Regulatory relationships of MST1

  • HK2 produced MSP and expressed RON in a form that was phosphorylated by rMSP [23].
  • On the contrary, MSP-induced IL-10 release is higher in AM from healthy non-smokers [24].
  • This caspase activation and apoptotic changes occur through JNK, since the co-expression of a dominant-negative mutant of JNK inhibited MST1-induced morphological changes as well as caspase activation [25].
  • In this study, we evaluated whether IL-15 regulates the macrophage stimulatory pathways governing inflammatory events that take place in the lung of patients with HIV infection [26].

Other interactions of MST1

  • 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 [17].
  • The beta-chain of MSP has three extra cysteines, Cys527, Cys562, and Cys672, which are not found in the plasminogen beta-chain [27].
  • Further, MSP-dependent beta4 tyrosine phosphorylation evokes p38 and NF-kappaB signaling required for keratinocyte wound closure [21].
  • Besides inducing interleukin-1 beta (IL-1beta) and interleukin-10 (IL-10) production, MSP triggers an enhanced tumor necrosis factor-alpha release, especially in healthy and pulmonary fibrosis smokers [24].
  • MSP activates the transcription factor NF-kappaB; this effect is more potent in healthy and fibrosis smokers (2.5-fold increase in p50 subunit translocation) [24].
  • Accordingly, MST1 mediates the nuclear translocation of FOXO1 in primary rat cerebellar granule neurons that are deprived of neuronal activity [28].

Analytical, diagnostic and therapeutic context of MST1

  • The ability of ron-sema to suppress growth of MSP-responsive cells in culture, including cancer cells, points to a potential therapeutic use of this molecule, and forced expression of it could potentially be used as a gene therapy tool for treating MSP-dependent types of cancer [29].
  • MSP protein was evaluated by Western blot in supernatant of cultured human tubular cells (HK2) and human mesangial cells (HMC) [23].
  • MSP mRNA was investigated in HK2 by reverse transcription-polymerase chain reaction (RT-PCR) [23].
  • The expression of MSP and RON in normal human renal tissue was studied by immunohistochemistry [23].
  • This was reflected in Northern blots probed with an MSP cDNA, which showed more than one mRNA species [2].


  1. Therapeutic Implications of a Human Neutralizing Antibody to the Macrophage-Stimulating Protein Receptor Tyrosine Kinase (RON), a c-MET Family Member. O'toole, J.M., Rabenau, K.E., Burns, K., Lu, D., Mangalampalli, V., Balderes, P., Covino, N., Bassi, R., Prewett, M., Gottfredsen, K.J., Thobe, M.N., Cheng, Y., Li, Y., Hicklin, D.J., Zhu, Z., Waltz, S.E., Hayman, M.J., Ludwig, D.L., Pereira, D.S. Cancer Res. (2006) [Pubmed]
  2. Cloning, sequencing, and expression of human macrophage stimulating protein (MSP, MST1) confirms MSP as a member of the family of kringle proteins and locates the MSP gene on chromosome 3. Yoshimura, T., Yuhki, N., Wang, M.H., Skeel, A., Leonard, E.J. J. Biol. Chem. (1993) [Pubmed]
  3. Characterization of the DNF15S2 locus on human chromosome 3: identification of a gene coding for four kringle domains with homology to hepatocyte growth factor. Han, S., Stuart, L.A., Degen, S.J. Biochemistry (1991) [Pubmed]
  4. The macrophage stimulating protein/RON system: a potential novel target for prevention and treatment of endometriosis. Matsuzaki, S., Canis, M., Pouly, J.L., Dechelotte, P., Okamura, K., Mage, G. Mol. Hum. Reprod. (2005) [Pubmed]
  5. Differential screening of a human chromosome 3 library identifies hepatocyte growth factor-like/macrophage-stimulating protein and its receptor in injured lung. Possible implications for neuroendocrine cell survival. Willett, C.G., Smith, D.I., Shridhar, V., Wang, M.H., Emanuel, R.L., Patidar, K., Graham, S.A., Zhang, F., Hatch, V., Sugarbaker, D.J., Sunday, M.E. J. Clin. Invest. (1997) [Pubmed]
  6. A comparison of speech perception of cochlear implantees using the Spectral Maxima Sound Processor (SMSP) and the MSP (MULTIPEAK) processor. McKay, C.M., McDermott, H.J., Vandali, A.E., Clark, G.M. Acta Otolaryngol. (1992) [Pubmed]
  7. A study of the unidimensionality and cumulativeness of the MOS Short-form General Health Survey. Moorer, P., Suurmeijer, T.P. Psychological reports. (1994) [Pubmed]
  8. Identification of the ron gene product as the receptor for the human macrophage stimulating protein. Wang, M.H., Ronsin, C., Gesnel, M.C., Coupey, L., Skeel, A., Leonard, E.J., Breathnach, R. Science (1994) [Pubmed]
  9. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Ghigna, C., Giordano, S., Shen, H., Benvenuto, F., Castiglioni, F., Comoglio, P.M., Green, M.R., Riva, S., Biamonti, G. Mol. Cell (2005) [Pubmed]
  10. Macrophage stimulating protein: purification, partial amino acid sequence, and cellular activity. Skeel, A., Yoshimura, T., Showalter, S.D., Tanaka, S., Appella, E., Leonard, E.J. J. Exp. Med. (1991) [Pubmed]
  11. Macrophage-stimulating protein and its receptor in non-small-cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration. Willett, C.G., Wang, M.H., Emanuel, R.L., Graham, S.A., Smith, D.I., Shridhar, V., Sugarbaker, D.J., Sunday, M.E. Am. J. Respir. Cell Mol. Biol. (1998) [Pubmed]
  12. Mefloquine-resistant falciparum malaria on the Thai-Burmese border. Nosten, F., ter Kuile, F., Chongsuphajaisiddhi, T., Luxemburger, C., Webster, H.K., Edstein, M., Phaipun, L., Thew, K.L., White, N.J. Lancet (1991) [Pubmed]
  13. Frequent hypermethylation of 5' flanking region of TIMP-2 gene in cervical cancer. Ivanova, T., Vinokurova, S., Petrenko, A., Eshilev, E., Solovyova, N., Kisseljov, F., Kisseljova, N. Int. J. Cancer (2004) [Pubmed]
  14. Oxygen yield and thermoluminescence characteristics of a cyanobacterium lacking the manganese-stabilizing protein of photosystem II. Burnap, R.L., Shen, J.R., Jursinic, P.A., Inoue, Y., Sherman, L.A. Biochemistry (1992) [Pubmed]
  15. Sensitivity of Plasmodium falciparum to mefloquine-sulphadoxine-pyrimethamine (Fansimef) in vivo and to mefloquine alone in vitro in Nigeria. Salako, L.A., Aderounmu, A.F., Laoye, J.O., Makinde, J.M., Adio, R.A. Ann. Trop. Med. Parasitol. (1988) [Pubmed]
  16. Death-associated protein 4 binds MST1 and augments MST1-induced apoptosis. Lin, Y., Khokhlatchev, A., Figeys, D., Avruch, J. J. Biol. Chem. (2002) [Pubmed]
  17. Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility. Sakamoto, O., Iwama, A., Amitani, R., Takehara, T., Yamaguchi, N., Yamamoto, T., Masuyama, K., Yamanaka, T., Ando, M., Suda, T. J. Clin. Invest. (1997) [Pubmed]
  18. Repression of the MSP/MST-1 gene contributes to the antiapoptotic gain of function of mutant p53. Zalcenstein, A., Weisz, L., Stambolsky, P., Bar, J., Rotter, V., Oren, M. Oncogene (2006) [Pubmed]
  19. Kinases involved in MSP/RON signaling. Danilkovitch, A., Leonard, E.J. J. Leukoc. Biol. (1999) [Pubmed]
  20. alpha 1-Antichymotrypsin is the human plasma inhibitor of macrophage ectoenzymes that cleave pro-macrophage stimulating protein. Skeel, A., Leonard, E.J. J. Biol. Chem. (2001) [Pubmed]
  21. The MSP receptor regulates alpha6beta4 and alpha3beta1 integrins via 14-3-3 proteins in keratinocyte migration. Santoro, M.M., Gaudino, G., Marchisio, P.C. Dev. Cell (2003) [Pubmed]
  22. Production and characterization of monoclonal antibodies to shark cartilage proteoglycan. Alves, M.L., Straus, A.H., Takahashi, H.K., Michelacci, Y.M. Braz. J. Med. Biol. Res. (1994) [Pubmed]
  23. Macrophage-stimulating protein is produced by tubular cells and activates mesangial cells. Rampino, T., Collesi, C., Gregorini, M., Maggio, M., Soccio, G., Guallini, P., Dal Canton, A. J. Am. Soc. Nephrol. (2002) [Pubmed]
  24. Macrophage-stimulating protein differently affects human alveolar macrophages from smoker and non-smoker patients: evaluation of respiratory burst, cytokine release and NF-kappaB pathway. Gunella, G., Bardelli, C., Amoruso, A., Viano, I., Balbo, P., Brunelleschi, S. Br. J. Pharmacol. (2006) [Pubmed]
  25. MST1-JNK promotes apoptosis via caspase-dependent and independent pathways. Ura, S., Masuyama, N., Graves, J.D., Gotoh, Y. Genes Cells (2001) [Pubmed]
  26. CD8 T-cell infiltration in extravascular tissues of patients with human immunodeficiency virus infection. Interleukin-15 upmodulates costimulatory pathways involved in the antigen-presenting cells-T-cell interaction. Agostini, C., Zambello, R., Facco, M., Perin, A., Piazza, F., Siviero, M., Basso, U., Bortolin, M., Trentin, L., Semenzato, G. Blood (1999) [Pubmed]
  27. Characterization of free alpha- and beta-chains of recombinant macrophage-stimulating protein. Yoshikawa, W., Hara, H., Takehara, T., Shimonishi, M., Sakai, H., Shimizu, N., Shimizu, S., Wang, M.H., Hagiya, M., Skeel, A., Leonard, E.J. Arch. Biochem. Biophys. (1999) [Pubmed]
  28. Regulation of neuronal cell death by MST1-FOXO1 signaling. Yuan, Z., Lehtinen, M.K., Merlo, P., Villén, J., Gygi, S., Bonni, A. J. Biol. Chem. (2009) [Pubmed]
  29. The soluble sema domain of the RON receptor inhibits macrophage-stimulating protein-induced receptor activation. Angeloni, D., Danilkovitch-Miagkova, A., Miagkov, A., Leonard, E.J., Lerman, M.I. J. Biol. Chem. (2004) [Pubmed]
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