Proteolytic cleavage and activation of pro-macrophage-stimulating protein by resident peritoneal macrophage membrane proteases.

Wang, Ming-Hai; Skeel, Alison; Leonard, Edward J.

doi:10.1172/jci118470

Cited by 71 publications

(81 citation statements)

References 32 publications

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“…Previous studies have identified a cell-surface, trypsin-fold serine protease activity on macrophages that activates MSP-1, potentiating MSP-1 binding to RON and subsequent macrophage activation (18-20). (Table 1), and (iii) MT-SP1 and RON are coexpressed in both peritoneal macrophages and cancer tissues, consistent with previous observations that MSP-1 is activated at the surface of cells that respond to MSP-1 (20). Activation of MSP-1 is the result of proteolysis C-terminal to R 483 (21).…”

Section: Mt-sp1 Is Present On the Cell Surface Of Peritoneal Macrophasupporting

confidence: 90%

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Bhatt

Welm

Farady

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

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A multidisciplinary method combining transcriptional data, specificity profiling, and biological characterization of an enzyme may be used to predict novel substrates. By integrating protease substrate profiling with microarray gene coexpression data from nearly 2,000 human normal and cancerous tissue samples, three fundamental components of a protease-activated signaling pathway were identified. We find that MT-SP1 mediates extracellular signaling by regulating the local activation of the prometastatic growth factor MSP-1. We demonstrate MT-SP1 expression in peritoneal macrophages, and biochemical methods confirm the ability of MT-SP1 to cleave and activate pro-MSP-1 in vitro and in a cellular context. MT-SP1 induced the ability of MSP-1 to inhibit nitric oxide production in bone marrow macrophages. Addition of HAI-1 or an MT-SP1-specific antibody inhibitor blocked the proteolytic activation of MSP-1 at the cell surface of peritoneal macrophages. Taken together, our work indicates that MT-SP1 is sufficient for MSP-1 activation and that MT-SP1, MSP-1, and the previously shown MSP-1 tyrosine kinase receptor RON are required for peritoneal macrophage activation. This work shows that this triad of growth factor, growth factor activator protease, and growth factor receptor is a protease-activated signaling pathway. Individually, MT-SP1 and RON overexpression have been implicated in cancer progression and metastasis. Transcriptional coexpression of these genes suggests that this signaling pathway may be involved in several human cancers.cancer ͉ macrophage activation ͉ protease substrate specificity ͉ proteomics D espite the successful physiological and biochemical characterization of many proteases, the vast majority of the Ͼ2% of the human genome that encodes proteases has yet to be functionally classified. Although many approaches demonstrate the sufficiency of a protease to cleave a given substrate, very few are able to address the physiological relevance of such in vitro findings. Cell-surface proteolysis is suggested to play a major role in cancer progression and metastasis through the processing of macromolecules important for regulating the extracellular environment. The cell-surface localization, high activity, and exquisite specificity of type II transmembrane serine proteases (TTSPs) suggest a role in outside-in signaling and interaction with the microenvironment. We elected to apply a multifaceted approach to identify physiologically relevant substrates of one prominent member of this family, membrane type serine protease 1 (MT-SP1/matriptase).Members of the TTSP family, such as hepsin and MT-SP1, are highly expressed in many cancers, including those of the prostate, breast, colon, and ovary (1-9). Both overexpression and inhibition studies have supported the role of MT-SP1 in tumorigenesis and tumor growth. Targeted overexpression of MT-SP1 in squamous epithelia in mice results in skin-limited nodules of squamous cell carcinoma that become metastatic in the presence of the chemical carcinogen DMBA (10). ...

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Section: Mt-sp1 Is Present On the Cell Surface Of Peritoneal Macrophasupporting

confidence: 90%

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Bhatt

Welm

Farady

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

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“…Several aspects of MSP activation and signaling make it an attractive functional candidate for IBD. First, proteolytic activation of MSP have been proposed to occur in areas of active inflammation through cell-surface proteases located on macrophages (38), (39). Second, while MSP was originally identified as a protein that could elicit macrophage chemotaxis and activation, signaling though the MSP/MST1R has recently been shown to inhibit LPS or cytokine mediated production of inflammatory mediators (such as NO, COX2, PGE2 and IL-12p40) by macrophages, through the inhibition of NfkB signaling (24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

“…MSP is secreted as a biologically inactive single chain precursor (pro-MSP) by the liver, and can be activated through proteolytic cleavage by serine proteases in areas of blood coagulation and active inflammation (38). Although the specific activating protease is unknown, a role for macrophage cell-surface proteases has been suggested from in vitro studies with cultured peritoneal macrophages and isolated macrophage membranes (39). MSP is the only known ligand for the MST1R, also known as RON receptor, a disulphide-linked heterodimer composed of an extracellular α chain and a transmembrane β chain with intrinsic kinase activity, expressed predominantly on tissue resident (differentiated) macrophages and epithelial cells (40).…”

Section: The Associated R689c Variant and Mst1 Functionmentioning

confidence: 99%

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

Goyette

Lefèbvre

et al. 2008

Mucosal Immunology

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Association mapping and candidate gene studies within IBD linkage regions, as well as genomewide association studies in CD have led to the discovery of multiple risk genes, but these only Corresponding author: John D. Rioux, Montreal Heart Institute, 5000 Belanger Street, Montreal, Quebec, Canada, H1T 1C8, rioux@inflammgen.org. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript explain a fraction of the genetic susceptibility observed in IBD. We have thus been pursuing a region on chromosome 3p21-22 showing linkage to CD and UC using a gene-centric association mapping approach. We identified twelve functional candidate genes by searching for literature cocitations with relevant keywords and for gene expression patterns consistent with immune/ intestinal function. We then performed an association study composed of a screening phase, where tagging SNPs were evaluated in 1020 IBD patients, and an independent replication phase in 745 IBD patients. These analyses identified and replicated significant association to IBD for four SNPs within a 1.2 Mb LD region. We then identified a non-synonymous coding variant (rs3197999, R689C) in the macrophage stimulating 1 (MST1) gene (p-value 3.62×10−6) that accounts for the association signal, and shows association to both CD and UC. MST1 encodes MSP, a protein regulating the innate immune responses to bacterial ligands. R689C is predicted to interfere with MSP binding to its receptor, suggesting a role for this gene in the pathogenesis of IBD.

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“…The level is not changed in the course of an acute phase reaction (21). To act on target cells in extravascular sites, pro-MSP must diffuse into tissues and be proteolytically cleaved to the biologically active disulfide-linked ␣␤ chain heterodimer (22). The EC 50 for the action of the MSP heterodimer on macrophages is 0.25 nM (1).…”

Section: Macrophage Stimulating Protein (Msp)mentioning

confidence: 99%

“…Several such proteases of the coagulation system, including factors XIa and XIIa and serum kallikrein cleave pro-MSP to active MSP in vitro (23). However, cleavage is minimal when blood clots, indicating that pro-MSP is not a preferred substrate for these enzymes (22). We have described two pro-MSP convertase activities in extravascular sites, one in wound fluid exudates (20) and the other associated with murine resident peritoneal macrophages (22).…”

Section: Macrophage Stimulating Protein (Msp)mentioning

confidence: 99%

α1-Antichymotrypsin Is the Human Plasma Inhibitor of Macrophage Ectoenzymes That Cleave Pro-macrophage Stimulating Protein

Skeel

Leonard

2001

Journal of Biological Chemistry

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Proteolytic cleavage and activation of pro-macrophage-stimulating protein by resident peritoneal macrophage membrane proteases.

Cited by 71 publications

References 32 publications

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

α1-Antichymotrypsin Is the Human Plasma Inhibitor of Macrophage Ectoenzymes That Cleave Pro-macrophage Stimulating Protein

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