Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine the regulation of type IV collagenase expression in murine peritoneal macrophages (PEM) after they are incubated with LPS. LPS stimulated the production of the latent forms of 92-kDa (MMP-9) and 72-kDa (MMP-2) type IV gelatinases in a dose-dependent (> 10 ng/ml) and serum-dependent manner. Time course analyses revealed that LPS regulated the expression of MMP-9 and MMP-2 via discordant kinetics. Prolonged treatment of PEM with LPS decreased MMP-9 but not MMP-2 activities. IFN-gamma decreased the production of both gelatinases by PEM responding to LPS. TGF-beta stimulated production of both matrix metalloproteinases but blocked the LPS-mediated secretion of MMP-9. LPS-stimulated MMP-9 production was suppressed by genistein and tyrphostin, two specific tyrosine kinase inhibitors, as well as H-7, a serine/threonine protein kinase inhibitor, but not by HA1004, a relatively selective inhibitor for PKA and PKG. Our data demonstrate that the secretion of MMP-2 and MMP-9 by murine PEM is differentially regulated, suggesting a distinct in vivo role for these two otherwise analogous type IV gelatinases in macrophage-mediated connective tissue destruction at sites of immunologic challenges.
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PMID:Regulatory mechanisms for the expression of type IV collagenases/gelatinases in murine macrophages. 814 39

PD 166285, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido[2,3-d]pyrimidines, was synthesized as the most potent and soluble analog of a series of small molecules originally identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 166285 was found to inhibit Src nonreceptor tyrosine kinase, fibroblast growth factor receptor-1, epidermal growth factor receptor and platelet-derived growth factor receptor beta subunit (PDGFR-beta), tyrosine kinases with half-maximal inhibitory potencies (IC50 values) of 8.4 +/- 2.3 nM (n = 6), 39.3 +/- 2.8 nM (n = 16), 87.5 +/- 13.7 nM (n = 6) and 98.3 +/- 7.9 nM (n = 16), respectively. PD 166285 also demonstrated inhibitory activity against mitogen-activated protein kinase (IC50 = 5 microM) and protein kinase C (IC50 = 22.7 microM). PD 166285 was further characterized as an ATP competitive inhibitor of Src nonreceptor tyrosine kinase, PDGFR-beta, fibroblast growth factor receptor-1 and epidermal growth factor receptor tyrosine kinases. In addition, PD 166285 inhibited PDGF- and EGF-stimulated receptor autophosphorylation in vascular smooth muscle cells (VSMCs) and A431 cells, respectively, and basic fibroblast growth factor-mediated tyrosine phosphorylation in Sf9 cells, with IC50 values of 6.5 nM, 1.6 microM and 97.3 nM, respectively, further establishing a tyrosine kinase mechanism of inhibition. The inhibition of PDGF receptor autophosphorylation in VSMCs by PD 166285 was long lasting and persisted for 4 days after a single 1-hr exposure followed by extensive washing. The PDGF-induced tyrosine phosphorylation of the 44- and 42-kDa mitogen-activated protein kinase isoforms was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 166285 in VSMCs. The effects of PD 166285 were also demonstrated in functional assays of cell attachment, migration and proliferation, in which vascular cell adhesion to vitronectin, PDGF-directed chemotaxis and serum-stimulated cell growth were all potently inhibited with IC50 values of 80 yo 120 nM. Finally, PD 166285 uniquely demonstrated potent inhibition of phorbol ester-induced production of 92-kDa gelatinase A (MMP-9) in VSMC without affecting 72-kDa gelatinase B (MMP-2) as measured by gelatin zymography. These results highlight the biological characteristics of PD 166285 as a broadly active protein tyrosine kinase capable of potently inhibiting a number of kinase mediated cellular functions, including cell attachment, movement and replication. The potential therapeutic utility of this broadly acting inhibitor as an antiproliferative and antimigratory agent could extend to such diseases as cancer, atherosclerosis and restenosis, in which redundancies in protein kinase signaling pathways are known to exist.
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PMID:In vitro pharmacological characterization of PD 166285, a new nanomolar potent and broadly active protein tyrosine kinase inhibitor. 940 19

Prostaglandin E(2) (PGE(2)) acts as a potent stimulator of bone resorption. In this study, we first clarified in normal ddy mice the involvement of protein kinase A and induction of matrix metalloproteinases (MMPs) in PGE(2)-induced bone resorption, and then identified PGE receptor subtype(s) mediating this PGE(2) action using mice lacking each subtype (EP1, EP2, EP3, and EP4) of PGE receptor. In calvarial culture obtained from normal ddy mice, both PGE(2) and dibutyryl cyclic AMP (Bt(2)cAMP) stimulated bone resorption and induced MMPs including MMP-2 and MMP-13. Addition of an inhibitor of protein kinase A, H89, or an inhibitor of MMPs, BB94, significantly suppressed bone-resorbing activity induced by PGE(2.) In calvarial culture from EP1-, EP2-, and EP3-knockout mice, PGE(2) stimulated bone resorption to an extent similar to that found in calvaria from the wild-type mice. On the other hand, a marked reduction in bone resorption to PGE(2) was found in the calvarial culture from EP4-knockout mice. The impaired bone resorption to PGE(2) was also detected in long bone cultures from EP4-knockout mice. Bt(2)cAMP greatly stimulated bone resorption similarly in both wild-type and EP4-knockout mice. Induction of MMP-2 and MMP-13 by PGE(2) was greatly impaired in calvarial culture from EP4-knockout mice, but Bt(2)cAMP stimulated MMPs induction similarly in the wild-type and EP4-knockout mice. These findings suggest that PGE(2) stimulates bone resorption by a cAMP-dependent mechanism via the EP4 receptor.
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PMID:Impaired bone resorption to prostaglandin E2 in prostaglandin E receptor EP4-knockout mice. 1074 73

Membrane type 1-matrix metalloproteinase (MT1-MMP)-mediated activation of MMP-2 is thought to be important in the proteolysis of extracellular matrix in pathological events in which monocytes/macrophages are found. Here we report on the induction and regulation of human monocyte MT1-MMP and its role in MMP-2 activation. Activation of monocytes by lipopolysaccharide resulted in the induction of MT1-MMP mRNA and protein that was suppressed by inhibitors of prostaglandin synthesis (indomethacin), adenylyl cyclase (SQ 22536), and protein kinase A (Rp-cAMPs). Suppression of MT1-MMP by indomethacin and SQ 22536 was reversed by prostaglandin E(2) and dibutyryl cyclic AMP, respectively, demonstrating that induction of monocyte MT1-MMP is regulated through a prostaglandin-cAMP pathway. Functional analysis revealed that pro-MMP-2 in the supernatants from human bone marrow stromal fibroblasts, normal male-derived fibroblasts and melanoma cells (A2058) was converted to active MMP-2 when cultured with activated but not control monocytes. Antibodies against MT1-MMP blocked the activation of MMP-2. Tissue inhibitor of metalloproteinase-2 regulation of MMP-2 activation was shown through the addition of varying amounts of recombinant tissue inhibitor of metalloproteinase-2 with pro-MMP-2 to MT1-MMP-expressing monocytes. These findings demonstrate that activated monocytes express functionally active MT1-MMP that may play a significant role in the activation of MMP-2 produced by other cells and as such influence developmental and pathological conditions.
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PMID:Monocyte membrane type 1-matrix metalloproteinase. Prostaglandin-dependent regulation and role in metalloproteinase-2 activation. 1125 24

Immunohistochemical studies using a polyclonal antibody, raised against the recombinant form of dentin matrix protein 1 (DMP1), show that DMP1 was detected mainly in odontoblasts in cultured mouse embryonic tooth germs. However, in restricted areas, DMP1 staining was also observed in secretory ameloblasts, in the stratum intermedium and stellate reticulum, but only when the odontoblasts located in front of them were unstained. When the embryonic tooth germs were cultured in the presence of inositol hexasulfate, a casein kinase I and II inhibitor, staining of odontoblasts was weak or nil, whereas, in contrast, ameloblasts and enamel organ were strongly immunolabelled, suggesting an enhanced translocation of DMP1 after secretion to the secretory ameloblasts and/or stratum intermedium and stellate reticulum. Moreover, DMP1--was shown to be a good substrate for gelatinase A (MMP-2), but not to gelatinase B (MMP- 9). We hypothesized that DMP1--or the sub-fractions cleaved by the MMP--could behave as diffusible signaling molecule (s) rather than as a true dentin extracellular matrix component.
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PMID:Inositol hexasulphate, a casein kinase inhibitor, alters the distribution of dentin matrix protein 1 in cultured embryonic mouse tooth germs. 1145 52

In the serum-free culture medium of bovine odontoblasts we detected active gelatinolytic metalloproteinases, matrix metalloproteinase (MMP)-2 and MMP-9 (gelatinases A and B). The activity of MMP-2, in particular, appeared suddenly around day 21 in the culture, coinciding with the development of odontoblastic cell processes and the loss of alkaline phosphatase. Reverse transcriptase-polymerase chain reaction analysis of these odontoblasts demonstrated that messages of MMP-2 but not MMP-9 increased significantly between day 15 and day 21. The in vitro observation indicates that medium conditioned by these odontoblasts and containing significant amounts of MMP-2 degrades not only the collagenous substrates but also purified dentin phosphophoryn as well. We have also observed that dephosphorylated dentin phosphoprotein becomes a better substrate for casein kinase II after limited proteolysis with MMP-2. These results support our working hypothesis that MMP-2-mediated proteolytic processing is an important step in accelerating the process of dentin matrix maturation, which includes phosphorylation and subsequent mineralization. As has been suggested previously, extracellular phosphorylation of matrix proteins is an important step in biomineralization both in bone and in dentin (Mikuni-Takagaki et al., J Bone Miner Res 1995;10:231-42; Zhu et al., Biochem J 1997; 323:637-43). Our present histochemical analysis in MMP-2 knockout mice confirms the concept with the delayed formation of mineralized tissues, dentin, and bone.
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PMID:Matrix metalloproteinase-2 in dentin matrix mineralization. 1150 97

We recently reported that matrix metalloproteinase 2 (MMP-2, gelatinase A) cleaves big endothelin 1 (ET-1), yielding the vasoactive peptide ET-1[1-32]. We tested whether ET-1[1-32] could affect the adhesion of human neutrophils to coronary artery endothelial cells (HCAEC). ET-1[1-32] rapidly down-regulated the expression of L-selectin and up-regulated expression of CD11b/CD18 on the neutrophil surface, with EC50 values of 1-3 nM. These actions of ET-1[1-32] were mediated via ETA receptors and did not require conversion of ET-1[1-32] into ET-1 by neutrophil proteases, as revealed by liquid chromatography and mass spectroscopy. Moreover, ET-1[1-32] evoked release of neutrophil gelatinase B, which cleaved big ET-1 to yield ET-1[1-32], thus revealing a positive feedback loop for ET-1[1-32] generation. Up-regulation of CD11b/CD18 expression and gelatinase release was tightly associated with activation of extracellular signal-regulated kinase (Erk). Stimulation of Erk activity was due to activation of Ras, Raf-1, and MEK (MAPK kinase). ET-1[1-32] also produced slight increases in the expression of ICAM-1 and E-selectin on HCAEC, and markedly enhanced beta2 integrin-dependent adhesion of neutrophils to activated HCAEC. These results are the first indication that gelatinolytic MMPs via cleavage of big ET-1 to yield ET-1[1-32] activate neutrophils and promote leukocyte-endothelial cell adhesion and, consequently, neutrophil trafficking into inflamed tissues.
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PMID:Matrix metalloproteinases regulate neutrophil-endothelial cell adhesion through generation of endothelin-1[1-32]. 1164 Dec 50

Altered expression of alphav integrins plays a critical role in tumor growth, invasion, and metastasis. In this study, we show that normal human epithelial ovarian cell line, HOSE, and ovarian cancer cell lines, OVCA 429, OVCA 433, and OVHS-1, expressed alphav integrin and associated beta1, beta3, and beta5 subunits, but only ovarian cancer cell lines OVCA 429 and OVCA 433 expressed alphavbeta6 integrin. The expression of alphavbeta6 in OVCA 429 and OVCA 433 was far higher than alphavbeta3 and alphavbeta5 integrin and correlated with high p42/p44 mitogen activated protein kinase (MAPK) activity and high secretion of high molecular weight urokinase plasminogen activator (HMW-uPA), pro-metalloproteinase 2 and 9 (pro-MMP-9 and pro-MMP-2). In contrast to HOSE and OVHS 1, OVCA 433 and OVCA 429 exhibited approximately 2-fold more plasminogen-dependent [3H]-collagen type IV degradation. Plasminogen-dependent [3H]-collagen IV degradation was inhibited by inhibitor of uPA (amiloride) and MMP (phenanthroline) and by antibodies against uPA or MMP-9 or alphavbeta6 integrin, indicating the involvement of alphavbeta6 integrin, uPA and MMP-9 in the process. The alphavbeta6 correlated increase in HMW-uPA and pro-MMP secretion could be inhibited by tyrosine kinase inhibitor genistein or the MEK 1 inhibitor U0126, consistent with a role of active p42/44 MAPK in the elevation of uPA, MMP-9, and MMP-2 secretion. Under similar conditions, genistein and U0126 inhibited plasminogen-dependent [3H]-collagen type IV degradation. These data suggest that sustained elevation of p42/44 MAPK activity may be required for the co-expression of alphavbeta6 integrin, which in turn may regulate the malignant potential of ovarian cancer cells via proteolytic mechanisms.
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PMID:Association between alphavbeta6 integrin expression, elevated p42/44 kDa MAPK, and plasminogen-dependent matrix degradation in ovarian cancer. 1183 93

A rate-limiting step of tumor cell metastasis is matrix degradation by active matrix metalloproteinases (MMPs). It is known that reactive oxygen species are involved in tumor metastasis. Sustained production of H(2)O(2) by phenazine methosulfate (PMS) induced activation of pro-MMP-2 through the induction of membrane type 1-MMP (MT1-MMP) expression in HT1080 cells. MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 and -2 levels were changed negligibly by PMS. A one time treatment with H(2)O(2) did not induce activation of MMPs. It was also demonstrated that superoxide anions and hydroxyl radicals were not related to PMS action. PMS-induced pro-MMP-2 activation was regulated by the receptor tyrosine kinases, especially the receptors of platelet-derived growth factor and vascular endothelial growth factor, and downstream on the phosphatidylinositol 3-kinase/NF-kappa B pathway but not Ras, cAMP-dependent protein kinase, protein kinase C, and mitogen-activated protein kinases. PMS did not induce pro-MMP-2 activation in T98G and NIH3T3 cells. This may be related to a low level of MT1-MMP, indicating a threshold level of MT1-MMP is important for pro-MMP-2 activation. Furthermore, PMS increased cell motility and invasion but decreased cell-cell interaction. Cell-matrix interaction was not affected by PMS.
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PMID:Sustained production of H(2)O(2) activates pro-matrix metalloproteinase-2 through receptor tyrosine kinases/phosphatidylinositol 3-kinase/NF-kappa B pathway. 1205 32

Cardiac fibroblasts (CFs) produce extracellular matrix proteins and participate in the remodeling of the heart. It is unknown if brain natriuretic peptide (BNP) is synthesized by CFs and if BNP participates in the regulation of extracellular matrix turnover. In this study, we examined the production of BNP in adult canine CFs and the role of BNP and its signaling system on collagen synthesis and on the activation of matrix metalloproteinases (MMPs). BNP mRNA was detected in CFs, and a specific radioimmunoassay demonstrated that BNP(1-32) was secreted into the media at a rate of 11.2+/-1.0 pg/10(5) cells per 48 hours (mean+/-SEM). The amount of BNP secretion was significantly (P<0.01) augmented by 10(-7) mol/L tumor necrosis factor-alpha in a time-dependent manner. BNP significantly (P<0.01) inhibited de novo collagen synthesis as assessed by [3H]proline incorporation, whereas zymographic MMP-2 (gelatinase) abundance was significantly (P<0.05) stimulated by BNP between 10(-7) and 10(-6) mol/L. In addition, protein expression of MMP-1, -2, and -3 and membranous type-1 MMP was significantly increased by 10(-6) mol/L BNP. The cGMP analogue 8-bromo-cGMP (10(-4) mol/L) mimicked the BNP effect, whereas inhibition of protein kinase G by KT5823 (10(-6) mol/L) significantly (P<0.05) attenuated BNP-induced zymographic MMP-2 abundance. In summary, this study reports that BNP is present in cultured CFs and that BNP decreases collagen synthesis and increases MMPs via cGMP-protein kinase G signaling. These in vitro findings support a role for BNP as a regulator of myocardial structure via control of cardiac fibroblast function.
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PMID:Brain natriuretic Peptide is produced in cardiac fibroblasts and induces matrix metalloproteinases. 1248 Aug 6


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