Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane-type serine protease 1 (MT-SP1) was recently cloned, and we now report its biochemical characterization. MT-SP1 is predicted to be a type II transmembrane protein with an extracellular protease domain. This localization was experimentally verified using immunofluorescent microscopy and a cell-surface biotinylation technique. The substrate specificity of MT-SP1 was determined using a positional scanning-synthetic combinatorial library and substrate phage techniques. The preferred cleavage sequences were found to be (P4-(Arg/Lys)P3-(X)P2-(Ser)P1-(Arg)P1'-(Ala)) and (P4-(X)P3-(Arg/Lys)P2-(Ser)P1(Arg) P1'(Ala)), where X is a non-basic amino acid. Protease-activated receptor 2 (PAR2) and single-chain urokinase-type plasminogen activator are proteins that are localized to the extracellular surface and contain the preferred MT-SP1 cleavage sequence. The ability of MT-SP1 to activate PARs was assessed by exposing PAR-expressing Xenopus oocytes to the soluble MT-SP1 protease domain. The latter triggered calcium signaling in PAR2-expressing oocytes at 10 nm but failed to trigger calcium signaling in oocytes expressing PAR1, PAR3, or PAR4 at 100 nm. Single-chain urokinase-type plasminogen activator was activated using catalytic amounts of MT-SP1 (1 nm), but plasminogen was not cleaved under similar conditions. The membrane localization of MT-SP1 and its affinity for these key extracellular substrates suggests a role of the proteolytic activity in regulatory events.
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PMID:Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates. 1083 93

Protease-activated receptor 2 (PAR-2) has been implicated in the regulation of several cellular functions in the progression of cancer. It is reported that PAR-2 expression is significantly increased in human renal cell carcinoma (RCC) tissue compared with the adjacent non-neoplastic kidney tissue. However, the function of PAR-2 in regulating cell invasion and migration of RCC remains elusive. In this study, we found that PAR-2 was overexpressed in RCC cells. Activation of PAR-2 with PAR-2AP (PAR-2 agonist) enhanced the invasion and migration of RCC cells, and increased the expressions of MMP-13 and urokinase plasminogen activator (uPA). However, knockdown of PAR-2 by siRNA could intervene in all regulating effects of PAR-2AP. Furthermore, activation of PAR-2 induced the activation of PI3K and AKT, and PI3K/AKT inhibitor LY294002 attenuated the invasion and migration of RCC cells stimulated by PAR-2 activation. Altogether, our study demonstrates that PAR-2 stimulates the activation of PI3K/AKT pathway, subsequently increasing the expressions of MMP-13 and uPA, and thereby promotes the invasion and migration of RCC cells.
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PMID:Protease-activated receptor 2 enhances renal cell carcinoma cell invasion and migration via PI3K/AKT signaling pathway. 2577 77