MACROPHAGE STIMULATING PROTEIN (MSP) BINDS TO ITS RECEPTOR VIA THE MSP BETA-CHAIN

Macrophage stimulating protein (MSP) is a 78-kDa disulfide-linked hete rodimer belonging to the plasminogen-related kringle protein family. M SP activates the RON receptor protein-tyrosine kinase, which results i n cell migration, shape change, or proliferation. A structure-activity study of MSP was performed using pro-MSP, MSP, MSP alpha and beta cha ins, and a complex including the first two kringles and IgG Fc (MSP-NK 2). Radioiodinated MSP and MSP beta chain both bound specifically to R ON. 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 th e beta chain bound to RON and partially inhibited MSP-induced RON phos phorylation in kidney 293 cells, it did not induce RON phosphorylation . Pro-MSP, MSP alpha chain, or MSP-NK2 failed to activate RON, consist ent with their inability to bind to the RON receptor. Functional studi es showed that only MSP induced cell migration, and shape change in re sident macrophages, and growth of murine keratinocytes. Our data indic ate that the primary receptor binding domain is located in a region of the MSP beta chain, in contrast to structurally similar hepatocyte gr owth 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.