title: Plasminogen-Dependent Matriptase Activation Accelerates Plasmin Generation by Differentiating Primary Human Keratinocytes.
abstract: Pericellular plasmin generation, an important pathophysiological process, can be initiated and accelerated by the autoactivation of the type 2 transmembrane serine protease matriptase and subsequent activation of urokinase plasminogen activator. The link between matriptase and plasminogen was initially thought to be one-directional: from matriptase, through plasminogen activator, to plasminogen. However, in the current study, we now show that primary human keratinocytes that are undergoing calcium-induced differentiation can rapidly activate matriptase in response to serum treatment via a mechanism dependent on intracellular calcium, protein kinase C, and phosphatidylinositol 3-kinases-based signaling. The serum factor, responsible for the induction of matriptase zymogen activation, was shown to be plasminogen. A sub-pM concentration of plasminogen (but not plasmin) acting at the cell surface is sufficient to induce matriptase activation, suggesting high potency and specificity of the induction. After matriptase zymogen activation, a proportion of active matriptase is shed into extracellular milieu and returns to the cell surface to accelerate plasmin generation. The ability of plasminogen to induce matriptase zymogen activation and the subsequent acceleration of plasmin generation by active matriptase reveals a feed-forward mechanism that allows differentiating human keratinocytes to rapidly and robustly activate pericellular proteolysis.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chen
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Shi
authors.initials: S
authors.lastname: Yin
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Ying-Jung J
authors.initials: YJ
authors.lastname: Lai
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA. Electronic address: lincy@georgetown.edu.
authors.forename: Chen-Yong
authors.initials: CY
authors.lastname: Lin
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology*; D005341:Fibrinolysin / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000201:enzymology*; D010958:Plasminogen / Q000378:metabolism*; D059748:Proteolysis; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D010958:Plasminogen; D012697:Serine Endopeptidases; C485595:matriptase; D005341:Fibrinolysin