Macrophage Stimulating Protein (MSP): significance in cell biology, life science, and clinical medicine

  • Takashi Kato 1. Urological Oncology Branch, National Cancer Institute, National Institute of Health, Bethesda, MD, USA. 2. Department of Pharmacology, Faculty of Medicine, Kindai University, Osaka, Japan
Keywords: HLP, MSP, Ron


Macrophage stimulating protein (MSP) was discovered as a serum protein affecting macrophage motility, and found to be similar with a hepatocyte growth factor (HGF)-family molecule, HGF-liked protein (HLP). MSP/HLP has 45% sequence similarity with HGF. Inactive pro-MSP is synthesized by hepatocytes and released into the circulating blood, and its activation is regulated in disease pathologies such as in inflammation and cancer progression. Through binding to the RON receptor, MSP acts in innate-immune responses and anti-inflammation, and prevents the induction of iNOS, COX-2, and PGE2 in response to endotoxin and interferon-. Therefore, MSP is a crucial regulator of inflammation in multiple animal disease models of the liver, kidney, lung, gut and other organs. Also, MSP suppresses glucose production and negatively regulates the expression of gluconeogenic enzymes. HGF-Met and MSP-Ron signaling have analogous functions. In future, MSP/RON signaling becomes a new important drug target, especially for excess inflammation, and the inhibition of Ron inhibitors is expected for cancer therapy


1. Leonard EJ, Skeel A. A serum protein that stimulates macrophage movement, chemotaxis and spreading. Exp Cell Res 1976; 102: 434-38.
2. Han S, Stuart LA, Degen SJ. Characterization of the DNF15S2 locus on human chromosome 3: identification of a gene coding for four kringle domains with homology to hepatocyte growth factor. Biochemistry 1991; 30: 9768-80.
3. Shimamoto A, Kimura T, Matsumoto K, Nakamura T. Hepatocyte growth factor-like protein is identical to macrophage stimulating protein. FEBS Lett 1993; 333: 61-6.
4. Bezerra JA, Han S, Danton MJ, Degen SJ. Are hepatocyte growth factor-like protein and macrophage stimulating protein the same protein? Protein Sci 1993; 2: 666-8.
5. Wang MH, Ronsin C, Gesnel MC, Coupey L, Skeel A, Leonard EJ, et al. Identification of the ron gene product as the receptor for the human macrophage stimulating protein. Science 1994; 266: 117-9.
6. Ronsin C, Muscatelli F, Mattei MG, Breathnach R. A novel putative receptor protein tyrosine kinase of the met family. Oncogene 1993; 8: 1195-1202.
7. Wang MH, Julian FM, Breathnach R, Godowski PJ, Takehara T, Yoshikawa W, et al. Macrophage stimulating protein (MSP) binds to its receptor via the MSP beta chain. J Biol Chem 1997; 272: 16999-7004.
8. Matsumoto K, Kataoka H, Date K, Nakamura T. Cooperative interaction between alpha- and beta-chains of hepatocyte growth factor on c-Met receptor confers ligand-induced receptor tyrosine phosphorylation and multiple biological responses. J Biol Chem 1998; 273: 22913-20.
9. Gaudino G, Follenzi A, Naldini L, Collesi C, Santoro M, Gallo KA, et al. RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. EMBO J 1994; 13: 3524-32.
10. Gaudino G, Avantaggiato V, Follenzi A, Acampora D, Simeone A, Comoglio PM. The proto-oncogene RON is involved in development of epithelial, bone and neuro-endocrine tissues. Oncogene 1995; 11: 2627-37.
11. Skeel A, Leonard EJ. Action and target cell specificity of human macrophage-stimulating protein (MSP). J Immunol 1994; 152: 4618-23.
12. Iwama A, Wang MH, Yamaguchi N, Ohno N, Okano K, Sudo T, et al. Terminal differentiation of murine resident peritoneal macrophages is characterized by expression of the STK protein tyrosine kinase, a receptor for macrophage-stimulating protein. Blood 1995; 86: 3394-403.
13. Correll PH, Iwama A, Tondat S, Mayrhofer G, Suda T, Bernstein A. Deregulated inflammatory response in mice lacking the STK/RON receptor tyrosine kinase. Genes Funct 1997; 1: 69-83.
14. Morrison AC, Correll PH. 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. J Immunol 2002; 168: 853-60.
15. Stuart WD, Kulkarni RM, Gray JK, Vasiliauskas J, Leonis MA, Waltz SE. Ron receptor regulates Kupffer cell-dependent cytokine production and hepatocyte survival following endotoxin exposure in mice. Hepatology 2011; 53: 1618-28.
16. McDowell SA, Mallakin A, Bachurski CJ, Toney-Earley K, Prows DR, Bruno T, et al. The role of the receptor tyrosine kinase Ron in nickel-induced acute lung injury. Am J Respir Cell Mol Biol 2002; 26: 99-104.
17. Goyette P, Lefebvre C, Ng A, Brant SR, Cho JH, Duerr RH, et al. Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis. Mucosal Immunol 2008; 1: 131-8.
18. Rampino T, Soccio G, Gregorini M, Guidetti C, Marasà M, Maggio M, et al. Neutralization of macrophage-stimulating protein ameliorates renal injury in anti-thy 1 glomerulonephritis. J Am Soc Nephrol 2007; 18: 1486-96.
19. Funakoshi H, Nakamura T. Identification of HGF-like protein as a novel neurotrophic factor for avian dorsal root ganglion sensory neurons. Biochem Biophys Res Commun 2001; 283: 606-12.
20. Tsutsui S, Noorbakhsh F, Sullivan A, Henderson AJ, Warren K, Toney-Earley K, et al. RON-regulated innate immunity is protective in an animal model of multiple sclerosis. Ann Neurol 2005; 57: 883-95.
21. Lee ES, Kalantari P, Tsutsui Section S, Klatt A, Holden J, Correll PH, et al. RON receptor tyrosine kinase, a negative regulator of inflammation, inhibits HIV-1 transcription in monocytes/macrophages and is decreased in brain tissue from patients with AIDS. J Immunol 2004; 173: 6864-72
How to Cite
Kato, T. (2016). Macrophage Stimulating Protein (MSP): significance in cell biology, life science, and clinical medicine. Journal of Medical Practice and Review, 1(04), 34-39. Retrieved from