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

---

Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Unlike most other matrix metalloproteinases (MMPs) MMP-19 is expressed in undifferentiated basal keratinocytes of healthy human skin. The human keratinocyte cell line HaCaT, which like basal keratinocytes constitutively expresses MMP-19, down-regulated the expression of MMP-19 at high calcium concentrations. Calcium-regulation occurred through E-cadherin mediated cell-cell contacts because neutralizing anti-E-cadherin antibodies restored MMP-19 expression in high calcium. Overexpression of MMP-19 in HaCaT cells (HaCaT-WT) increased cellular proliferation, as well as migration and adhesion on type I collagen. This was due to proteolysis of the insulin-like growth factor (IGF) binding protein-3 by MMP-19, which augmented signaling through the IGF-I receptor, as evidenced by its increased autophosphorylation. Conversely, these effects were not observed in cells transfected with MMP-2 or a catalytically inactive MMP-19 mutant. As further proof that increased IGF-signaling promoted adhesion and migration in HaCaT-WT cells, we reproduced these effects by treating parental HaCaT with IGF-I. We observed dephosphorylation of the focal adhesion kinase in HaCaT-WT as well as IGF-I-treated HaCaT cells, suggesting that inactivating focal adhesion kinase is a mechanism by which IGF-I enhances adhesion. Furthermore, IGF-I-triggered motility on type I collagen was mediated by MMP activity, which, however, was distinct from MMP-19. Considering the coexpression of IGFBP-3 and MMP-19 in the skin, we conclude that MMP-19 is a likely candidate to be the major IGFBP-3 degrading MMP in the quiescent epidermis. This activity might have widespread consequences for the behavior of epidermal keratinocytes.
...
PMID:Matrix metalloproteinase 19 regulates insulin-like growth factor-mediated proliferation, migration, and adhesion in human keratinocytes through proteolysis of insulin-like growth factor binding protein-3. 1293 69

Premenopausal women have a lower cardiovascular risk and a higher incidence of several autoimmune diseases involving blood vessels than men. Although the precise effects of estrogens on the cardiovascular system are largely unknown, recent data suggest that estrogens can exert direct regulatory effects on endothelial cells. In the present study, we show that 17beta-estradiol increases human umbilical vein endothelial cell attachment to the extracellular matrix proteins laminin-1, type IV collagen, type I collagen, and fibronectin. Estradiol enhanced adhesion most significantly to laminin-1 and to fibronectin-derived synthetic peptides containing an RGD sequence. Upon exposure to estradiol, an increase in beta1, alpha5 and alpha6 integrin mRNA was observed in subconfluent cells which was abrogated by treatment with cycloheximide. This increase was followed by a later enhancement in surface expression of the above integrins. In addition, integrin-mediated signaling was also enhanced by estrogens since an increase in tyrosine-phosphorylation of focal adhesion kinase induced by cell attachment was observed in estrogen-treated endothelial cells. Since integrins have an important role in mediating endothelial cell attachment, migration and differentiation, the increase in integrin expression and function induced by estradiol may be an important mechanism through which estrogens can promote neovascularization and vessel repair.
...
PMID:Estradiol enhances endothelial cell interactions with extracellular matrix proteins via an increase in integrin expression and function. 1451 26

We have recently demonstrated that in breast carcinoma MCF7 cells MT1-MMP processes the alphav, alpha3, and alpha5 integrin precursors generating the respective mature S-S-linked heavy and light alpha-chains. The precursor of alpha2 integrin subunit was found resistant to MT1-MMP proteolysis. The processing of the alphav subunit by MT1-MMP facilitated alphavbeta3-dependent adhesion, activation of FAK signaling pathway, and migration of MCF7 cells on vitronectin. To elucidate further the effects of MT1-MMP on cellular integrins, we examined the functional activity of alpha5beta1 and alpha2beta1 integrins in MCF7 cells expressing MT1-MMP. Either expression of MT1-MMP alone or its coexpression with alphavbeta3 failed to affect the functionality of alpha5beta1 integrin, and adhesion of cells to fibronectin. MT1-MMP, however, profoundly affected the cross-talk involving alphavbeta3 and alpha2beta1 integrins. In MT1-MMP-deficient cells, integrin alphavbeta3 suppressed the functional activity of the collagen-binding alpha2beta1 integrin receptor and diminished cell adhesion to type I collagen. Coexpression of MT1-MMP with integrin alphavbeta3 restored the functionality of alpha2beta1 integrin and, consequently, the ability of MCF7 cells to adhere efficiently to collagen. We conclude that the MT1-MMP-controlled cross-talk between alphavbeta3 and alpha2beta1 integrins supports binding of aggressive, MT1-MMP-, and alphavbeta3 integrin-expressing malignant cells on type I collagen, the most common substratum of the extracellular matrix.
...
PMID:Membrane type-1 matrix metalloproteinase (MT1-MMP) processing of pro-alphav integrin regulates cross-talk between alphavbeta3 and alpha2beta1 integrins in breast carcinoma cells. 1459 17

The mechanisms involved in the mechanical loading-induced increase in bone formation remain unclear. In this study, we showed that cyclic strain (CS) (10 min, 1% stretch at 0.25 Hz) stimulated the proliferation of overnight serum-starved ROS 17/2.8 osteoblast-like cells plated on type I collagen-coated silicone membranes. This increase was blocked by MEK inhibitor PD-98059. Signaling events were then assessed 0 min, 30 min, and 4 h after one CS period with Western blotting and coimmunoprecipitation. CS rapidly and time-dependently promoted phosphorylation of both ERK2 at Tyr-187 and focal adhesion kinase (FAK) at Tyr-397 and Tyr-925, leading to the activation of the Ras/Raf/MEK pathway. Cell transfection with FAK mutated at Tyr-397 completely blocked ERK2 Tyr-187 phosphorylation. Quantitative immunofluorescence analysis of phosphotyrosine residues showed an increase in focal adhesion plaque number and size in strained cells. CS also induced both Src-Tyr-418 phosphorylation and Src to FAK association. Treatment with the selective Src family kinase inhibitor pyrazolopyrimidine 2 did not prevent CS-induced FAK-Tyr-397 phosphorylation suggesting a Src-independent activation of FAK. CS also activated proline-rich tyrosine kinase 2 (PYK2), a tyrosine kinase highly homologous to FAK, at the 402 phosphorylation site and promoted its association to FAK in a time-dependent manner. Mutation of PYK2 at the Tyr-402 site prevented the ERK2 phosphorylation only at 4 h. Intra and extracellular calcium chelators prevented PYK2 activation only at 4 h. In summary, our data showed that osteoblast response to mitogenic CS was mediated by MEK pathway activation. The latter was induced by ERK2 phosphorylation under the control of FAK and PYK2 phosphorylation orchestrated in a time-dependent manner.
...
PMID:Mechanical strain on osteoblasts activates autophosphorylation of focal adhesion kinase and proline-rich tyrosine kinase 2 tyrosine sites involved in ERK activation. 1509 2

The interactions of osteoblasts with their surrounding extracellular matrix (ECM) are essential for skeletal development, homeostasis, and maintenance of the mature osteoblastic phenotype. Integrins are the principal transducers of ECM signals that regulate this process of osteoblast commitment and differentiation. Several studies indicate that the alpha(2)beta(1) integrin interaction with type I collagen is a crucial signal for the induction of osteoblastic differentiation and matrix mineralization. Integrin alpha(2)beta(1) recognizes the Gly-Phe-Hyp-Gly-Glu-Arg (GFOGER) motif in residues 502-507 of the alpha(1)[I] chain of type I collagen. This study demonstrates that an alpha(2)beta(1) integrin-specific GFOGER peptide triggers the activation of focal adhesion kinase and alkaline phosphatase in MC3T3-E1 murine immature osteoblast-like cells, two events that have been implicated in the osteoblastic differentiation pathway. These GFOGER-peptide surfaces also support the expression of multiple osteoblast-specific genes, including osteocalcin and bone sialoprotein, and induce matrix mineralization in a manner similar to type I collagen. This triple-helical peptide represents a promising surface modification strategy for the design of collagen-mimetic bioadhesive surfaces that support osteoblastic differentiation.
...
PMID:Alpha2beta1 integrin-specific collagen-mimetic surfaces supporting osteoblastic differentiation. 1516

Bovine type I collagen (Col-I) is utilized for medical purposes such as cosmetic surgery and wrinkle removal. Cyclooxygenase-2 (COX-2) plays roles in pathophysiological processes including inflammation and tumorigenesis. This study examines the effects of Col-I on the COX-2 expression and the signaling pathways in macrophages. Col-I increased the levels of COX-2 protein and mRNA in serum-stimulated Raw264.7 cells in a time- and concentration-dependent manner. Treatment of cells with Col-I increased CCAAT/enhancer binding protein (C/EBP) DNA binding. Antibody supershift experiments revealed that C/EBP DNA binding activity induced by Col-I depended largely on C/EBPbeta and C/EBPdelta. Immunocytochemistry showed that Col-I induced nuclear translocation of C/EBPbeta and C/EBPdelta, whose activation contributes to COX-2 induction. Overexpression of the dominant-negative mutant form of C/EBP abolished COX-2 induction by Col-I. Col-I also increased cyclic-AMP response element binding protein (CREB) binding to DNA. Inhibition of focal adhesion kinase (FAK) or downstream phosphoinositide 3-kinase and p70S6 kinase by specific chemical inhibitors prevented COX-2 induction by Col-I, and C/EBP and CREB from binding to their consensus DNA oligonucleotides. Experiments using chemical inhibitors or dominant-negative mutant vectors showed that the mitogen-activated protein (MAP) kinase pathways including p38-kinase and extracellular signal-regulated kinase (ERK1/2), but not c-Jun N-terminal kinase (JNK1), simultaneously regulated COX-2 induction by Col-I. This was in agreement with inhibition of Col-I-inducible C/EBP and CREB DNA binding by concomitant treatment with SB203580 and PD98059. These results provide evidence that Col-I induces COX-2 in serum-stimulated macrophages and that the multiple cell signaling pathways involving Src-focal adhesion kinase, phosphoinositide 3-kinase, and MAP kinases regulate COX-2 induction by Col-I via C/EBP and CREB activation.
...
PMID:Induction of cyclooxygenase-2 by bovine type I collagen in macrophages via C/EBP and CREB activation by multiple cell signaling pathways. 1516 55

The beta(1) integrin, functioning as a mechanoreceptor, senses a mechanical stimulus generated during collagen matrix contraction and down-regulates the phosphatidylinositol 3-kinase (PI3K)/Akt survival signal triggering apoptosis. The identities of integrin-associated signal molecules in the focal adhesion complex that are responsible for propagating beta(1) integrin viability signals in response to collagen matrix contraction are not known. Here we show that in response to collagen contraction focal adhesion kinase (FAK) is dephosphorylated. In contrast, enforced activation of beta(1) integrin by anti-beta(1) integrin antibody, which protects fibroblasts from apoptosis, preserves FAK phosphorylation. We demonstrate that ligation of beta(1) integrin by type I collagen or by enforced activation of beta(1) integrin by antibody promotes phosphorylation of FAK, p85 subunit of PI3K, and serine 473 of Akt. Wortmannin inhibited Akt but not FAK phosphorylation in response to enforced activation of beta(1) integrin by antibody. Blocking FAK by pharmacologic inhibition or by dominant negative FAK attenuated phosphorylation of p85 subunit of PI3K and Akt. Dominant negative FAK augmented fibroblast apoptosis during collagen contraction, and this was associated with diminished Akt activity. Constitutively active FAK augmented levels of p85 subunit of PI3K and Akt phosphorylation, and fibroblasts were protected from apoptosis. Our data identify a novel role for FAK, functioning upstream of PI3K/Akt, in transducing a beta(1) integrin viability signal in collagen matrices.
...
PMID:Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. 1516 38

Viscoelastic properties of skin samples were measured in three types of mice (tight skin, Tsk, control and Mov-13), that are known to differ with regard to content of type I collagen. The experimental design used uniaxial stretching and measured the creep response and the complex compliance. The creep response was measured directly. The complex compliance was determined using a Wiener-Volterra constitutive model for each sample. The models were calculated from data obtained by applying a stress input having a pseudo-Gaussian waveform and measuring the strain response. The storage compliance of Mov-13 and control skin were similar and were greater than Tsk (p<0.001). The loss compliance of each group was significantly different (p<0.001) from each other group; Tsk had the lowest and control had the highest loss compliance. The phase angle of the Mov-13 and Tsk were similar and were less than the controls (p<0.001). The creep response was fit with a linear viscoelastic model. None of the parameters in the creep model differed between groups. The results indicate that gene-targeted and mutant animals have soft tissue mechanical phenotypes that differ in complex ways. Caution should be exercised when using such animals as models to explore the role of specific constituents on tissue properties.
...
PMID:Viscoelastic properties of skin in Mov-13 and Tsk mice. 1533 23

Previously, we showed that Janus kinase 2 (JAK2) is important in advanced glycation end-product (AGE)-induced effects in renal interstitial (NRK-49F) fibroblasts. Leptin is a JAK2-activating cytokine via the long form leptin receptor (Ob-Rb). Leptin and connective tissue growth factor (CTGF) may be involved in renal fibrosis. However, the relationship between leptin and CTGF in terms of AGE-induced effects remains unknown. Thus, the effects of AGE (150 microg/ml) and leptin on mitogenesis, CTGF and collagen expression in NRK-49F cells were determined. We found that leptin and AGE increased mitogenesis and type I collagen protein expression at 3 and 7 days, respectively. AGE increased leptin mRNA and protein expression at 2-3 days. AGE increased CTGF mRNA and protein expression at 3-5 days. AG-490 (JAK2 inhibitor) abrogated AGE-induced leptin mRNA and protein expression at 2-3 days. AG-490 and Ob-Rb anti-sense oligodeoxynucleotides (ODN) abrogated AGE-induced CTGF mRNA and protein expression at 3-5 days. AG-490 and CTGF anti-sense ODN abrogated AGE-induced mitogenesis and collagen protein expression at 7 days. Additionally, leptin dose (0.2-1 microg/ml) and time (1-2 days)-dependently increased CTGF protein expression. AG-490 abrogated leptin (1 microg/ml)-induced CTGF protein expression at 2 days. AG-490 and CTGF anti-sense ODN abrogated leptin-induced mitogenesis and collagen protein expression at 3 days. We concluded that AGE induced JAK2 to increase leptin while leptin induced JAK2 to increase CTGF-induced mitogenesis and type I collagen protein expression in NRK-49F cells. Additionally, AGE-induced mitogenesis and type I collagen protein expression were dependent on leptin-induced CTGF.
...
PMID:Leptin and connective tissue growth factor in advanced glycation end-product-induced effects in NRK-49F cells. 1538 80

Spaceflight leads to reduced bone mineral density in weight bearing bones that is primarily attributed to a reduction in bone formation. We have previously demonstrated severely reduced osteoblastogenesis of human mesenchymal stem cells (hMSC) following 7 days culture in modeled microgravity (MMG). One potential mechanism for reduced osteoblastic differentiation is disruption of type I collagen (Col I)-integrin interactions and reduced integrin signaling. Integrins are heterodimeric transmembrane receptors that bind extracellular matrix (ECM) proteins and produce signals essential for proper cellular function, survival, and differentiation. Therefore, we investigated the effects of MMG on integrin expression and function in hMSC. We demonstrate that 7 days of culture in MMG leads to reduced expression of the ECM protein, Col I. Conversely, MMG consistently increases Col I-specific alpha2 and beta1 integrin protein expression. Despite this increase in integrin subunit expression, autophosphorylation of adhesion-dependent kinases, focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2), is significantly reduced. Activation of Akt protein kinase (Akt) is unaffected by the reduction in FAK activation. However, reduced downstream signaling via the Ras-mitogen activated protein kinase (MAPK) pathway is evidenced by a reduction in Ras and extracellular signal-related protein kinase (ERK) activation. Taken together, our findings indicate that MMG decreases integrin/MAPK signaling, which likely contributes to the observed reduction in osteoblastogenesis.
...
PMID:Modeled microgravity disrupts collagen I/integrin signaling during osteoblastic differentiation of human mesenchymal stem cells. 1566 Apr 14


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---