Macrophage-Stimulating Protein Induces Proliferation and Migration of Murine Keratinocytes

Wang, Ming Hai; Dlugosz, Andrzej A.; Sun, Yi; Suda, Toshio; Skeel, Alison; Leonard, Edward J.

doi:10.1006/excr.1996.0200

Cited by 97 publications

(81 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Macrophages respond to MSP-1 via RON activation, leading to changes in cell shape and increased migration, as well as an inhibition of nitric oxide production (23)(24)(25). We found that primary mouse peritoneal macrophages, but not primary mouse bone marrow macrophages, underwent a characteristic shape change upon activation by MSP-1 ( Fig.…”

Section: Msp-1 Activation By Mt-sp1 Results In Macrophage Morphologymentioning

confidence: 74%

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

View full text Add to dashboard Cite

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). ...

show abstract

Section: Msp-1 Activation By Mt-sp1 Results In Macrophage Morphologymentioning

confidence: 74%

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

View full text Add to dashboard Cite

show abstract

“…This provides a mechanism for Ron activation by HGF in the case of MSP de®ciency during embryonic development. The response to HGF and MSP through the activation of Met and Ron is mediated by the same pathways, mainly by Ras and by PI-3 Kinase (Wang et al, 1996;Bardelli et al, 1999). Met can regulate growth and transformation by activating the MAP kinase cascade through Grb2/Sos/Ras complex whereas the Ron pathway is directed more towards cellular movement and matrix invasion (Santoro et al, 1996;Wang et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Cross-talk between the proto-oncogenes Met and Ron

et al. 2000

View full text Add to dashboard Cite

“…flRon activation, upon binding with its ligand (macrophage stimulating protein, MSP), promotes responses involved in normal development as well as tumorigenesis and metastasis, including cell proliferation, dissociation, motility, matrix invasion and morphological changes known as epithelial-mesenchymal transformation (EMT) (Wang et al, 1996;Danilkovitch-Miagkova et al, 2000Thiery, 2003). Notably, ligand activation of Stk, the murine ortholog of Ron, was also reported to induce apoptosis .…”

Section: Introductionmentioning

confidence: 99%

Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter

Angeloni

Danilkovitch‐Miagkova

Иванова

et al. 2007

Oncogene

View full text Add to dashboard Cite

The gene for tyrosine-kinase receptor Ron (MST1R) resides in the chromosome 3p21.3 region, frequently affected in common human malignancies. The gene generates two transcripts, 5 and 2 kb-long, full-length Ron (flRon) and short-form Ron (sfRon), respectively. Here, we show for the first time that the variegated Ron expression is associated with variations in the methylation patterns of two distinct CpG islands in Ron proximal promoter. Widespread hypermethylation associates with lack of flRon whereas hypermethylation of the distal island associates with transcription of sfRon, a constitutively active tyrosine-kinase that drives cell proliferation. sfRon inhibition with kinase-dead transgenes decreases cancer cell growth and induces cellular differentiation. sfRon could be a new drug target in cancer types in which it contributes to tumor progression.

show abstract

Macrophage-Stimulating Protein Induces Proliferation and Migration of Murine Keratinocytes

Cited by 97 publications

References 0 publications

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Cross-talk between the proto-oncogenes Met and Ron

Hypermethylation of Ron proximal promoter associates with lack of full-length Ron and transcription of oncogenic short-Ron from an internal promoter

Contact Info

Product

Resources

About