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Macrophage Stimulating Protein (Msp) Binds to Its Receptor Via the Msp Beta Chain

  1. Author:
    Wang, M. H.
    Julian, F. M.
    Breathnach, R.
    Godowski, P. J.
    Takehara, T.
    Yoshikawa, W.
    Hagiya, M.
    Leonard, E. J.
  2. Author Address

    Wang MH WAYNE STATE UNIV VA MED CTR DIV PULM MED B-4365 4646 JOHN RD DETROIT, MI 48201 USA NCI FREDERICK CANC RES & DEV CTR IMMUNOBIOL LAB FREDERICK, MD 21702 USA IMMUNOTECH SA ANTIBODY DEPT F-13276 MARSEILLE 09 FRANCE INST BIOL INSERM U211 F-44035 NANTES 01 FRANCE GENENTECH INC DEPT CELL GENET S SAN FRANCISCO, CA 94080 USA TOYOBO CO LTD OTSU SHIGA 52002 JAPAN
    1. Year: 1997
  1. Journal: Journal of Biological Chemistry
    1. 272
    2. 27
    3. Pages: 16999-17004
  2. Type of Article: Article
  1. Abstract:

    Macrophage stimulating protein (MSP) is a 78-kDa disulfide-linked heterodimer belonging to the plasminogen-related kringle protein family. MSP activates the RON receptor protein-tyrosine kinase, which results in cell migration, shape change, or proliferation. A structure-activity study of MSP was performed using pro-MSP, MSP, MSP alpha and beta chains, and a complex including the first two kringles and IgG Fc (MSP-NK2). Radioiodinated MSP and MSP beta chain both bound specifically to RON. The K-d of 1.4 nM for MSP beta chain is higher than the reported K-d range of 0.6-0.8 nM for MSP. Pro-MSP, MSP alpha chain, and MSP-NK2 did not bind. Only MSP stimulated RON autophosphorylation. Although the beta chain bound to RON and partially inhibited MSP-induced RON phosphorylation in kidney 293 cells, it did not induce RON phosphorylation. Pro-MSP, MSP alpha chain, or MSP-NK2 failed to activate RON, consistent with their inability to bind to the RON receptor. Functional studies showed that only MSP induced cell migration, and shape change in resident macrophages, and growth of murine keratinocytes. Our data indicate that the primary receptor binding domain is located in a region of the MSP beta chain, in contrast to structurally similar hepatocyte growth factor, in which the receptor binding site is in the alpha chain. However, full activation of RON requires binding of the complete MSP disulfide-linked alpha beta chain heterodimer. [References: 34]

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