Biologic Activities of Nonenzymatic Thrombin: Elucidation of a Macrophage Interactive Domain

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Abstract
Our studies to date have clearly demonstrated the existence of a unique cell interactive exosite region in thrombin, which mediates specific biologic effects on cells of monocytic-macrophage lineage. These findings are of potential physiologic significance, since even proteolytically degraded forms of thrombin (beta- and gamma-thrombin) or fragments of thrombin arising due to breakdown of thrombin-thrombomodulin complexes are potentially biologically active and are not subject to inhibition by inhibitors such as antithrombin III. Such degraded thrombin forms and proteolytic fragments are likely to be present at sites of inflammation and wound repair where they may be important modulators of macrophage-monocyte responsiveness. Importantly, as emphasized in this communication, the chemotactic and growth-promoting properties of this site, although overlapping, are clearly dissociable. It is apparent that the chemotactic effects require the presence of most, if not all, of the 338-400 sequence, whereas the mitogenic effects are mediated exclusively through the so-called loop B insertion sequence that is a unique feature of thrombin. Although there are ample precedents for differing functional domains within discrete proteins and the presence of hormonelike regions in proteins (such as fibronectin and immunoglobulin G) has been documented, it is fascinating to speculate how functionally unique regions such as this can arise. Data from Craik and associates suggest that unique amino acid sequences in proteins originate from gene insertions at intron-exon junctions and are characteristically surface expressed. These insertion sequences give rise to unique structural and functional features that characterize the particular protein, and also serve to differentiate it from other related members within its family.(ABSTRACT TRUNCATED AT 250 WORDS)

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