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

With respect to liver disease, the primary function of the laboratory is to identify its presence. Tests are not available that permit a specific diagnosis and an accurate prognosis. Several tests should be present in a minimum data base that can help identify hepatobiliary disease. They are ALT, SAP, total serum bilirubin, urine bilirubin, cholesterol, albumin, BUN, glucose, red cell morphology, and urine sediment. It is sometimes possible to tentatively identify whether a disease is primarily hepatocellular or biliary from the pattern of changes that occur in these tests. In addition, an estimate of the severity is sometimes possible when abnormal values are extreme. The keys are to avoid overinterpretation, use serial evaluations, and rely on a liver biopsy when definitive answers are needed. If liver disease is suspected but there are only marginal changes in the routine tests, the more sensitive tests of function, BSP retention and ammonia tolerance, are warranted. In the future, as more knowledge is gained about the responses of ARG, GGT, and ICG retention to naturally occurring diseases, these tests may join or replace some of those currently used. Also, as the ability to accurately and economically measure the various bile acids improves, a sensitive, yet noninvasive, method to detect and define modest changes in hepatobiliary function may result.
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PMID:Laboratory evaluation of liver disease. 387 5

Integrins are heterodimeric membrane receptors that mediate cell-extracellular matrix (ECM), and cell-cell interactions. Integrins provide a physical link between the ECM and the cell cytoskeleton, and transduce signals which lead to elevation of cytosolic pH and calcium levels, changes in phospholipid metabolism and ultimately regulate gene expression. Osteoclast bone resorption is a complicated multistep process, that starts with matrix recognition, osteoclast attachment, polarization and formation of the sealing zone on the bone, followed by the directional secretion of acids and lysosomal enzymes to the resorbing surface. Osteoclasts exhibit high expression of the alpha v beta 3 integrin, which binds to a variety of RGD-containing proteins including vitronectin, osteopontin and bone sialoprotein. RGD-containing peptides, RGD-mimetics and blocking antibodies to alpha v beta 3 integrins were shown to inhibit bone resorption in vitro and in vivo, suggesting that this integrin plays an important role in regulating osteoclast activity. Furthermore, RGD-containing peptides and proteins modulate osteoclastic cytosolic calcium levels. Phosphatidyl inositol 3-kinase and c-Src were co-immunoprecipitated with alpha v beta 3 integrins in these cells. In addition, c-Cbl was found to be a substrate of c-Src in osteoclasts. More recently, ligand-engagement or clustering of alpha v beta 3 integrins in osteoclasts induced tyrosine phosphorylation of PYK2, a member of the focal adhesion kinase family, and of p130cas, a substrate of v-Src and v-Crk. Both PYK2 and p130cas were also found in the sealing zone of actively resorbing osteoclasts. How these signaling molecules interact with each other in mediating the alpha v beta 3 rate limiting effect on bone resorption is not well understood. They emerged however as key players in linking the adhesion of osteoclasts to the bone matrix, to cytoskeletal organization, and to the polarization and activation of these cells for bone resorption.
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PMID:Integrin-mediated signaling in the regulation of osteoclast adhesion and activation. 968 33

Integrins are heterodimeric adhesion receptors that mediate cell-matrix and cell-cell interactions. Osteoclasts highly express the alphavbeta3 integrin, which binds to a variety of extracellular matrix proteins including vitronectin, osteopontin and bone sialoprotein. RGD-containing peptides, RGD-mimetics and alphavbeta3 blocking antibodies inhibit bone resorption in vitro and in vivo, suggesting that this integrin plays an important role in osteoclast function. RGD-containing peptides were shown to raise cytosolic calcium in osteoclasts. Furthermore, several signaling and adaptor molecules were found to be involved in alphavbeta3 integrin-dependent signaling pathways, including phosphatidylinositol 3-kinase, c-Src, PYK2 and p130(cas). In addition, cytoskeletal molecules such as paxillin, vinculin, gelsolin and F-actin are recruited to adhesion contacts upon integrin activation. Many of these molecules signaling and cytoskeletal localize to the sealing zone of actively resorbing osteoclasts, suggesting that they play a role in linking the adhesion of osteoclasts to the bone matrix with the cytoskeletal organization and the polarization and activation of these cells for bone resorption.
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PMID:Integrins and signaling in osteoclast function. 1084 93

Numerous bone matrix proteins can interact with alpha(v)-containing integrins including alpha(v)beta3. To elucidate the net effects of the interaction between these proteins and alpha(v)beta3 on osteoblast function, we developed a murine osteoblastic cell line that overexpressed human alpha(v)beta3. Human alpha(v)beta3-integrin was expressed on cell membrane, in which its presence did not alter the surface level of endogenous mouse alpha(v)beta3. The expressed human alpha(v)beta3 was functional because cell adhesion to osteopontin was increased and this increment was abolished by antibody against human alpha(v)beta3. The proliferation rate of cells overexpressing alpha(v)beta3 (alpha(v)beta3-cells) was increased whereas matrix mineralization was decreased. To elucidate the mechanisms leading to inhibition of matrix mineralization, the expression of proteins important for mineralization was analyzed. Alkaline phosphatase activity and the expression of osteocalcin, type I collagen, and bone sialoprotein (BSP) were decreased whereas osteopontin was stimulated in alpha(v)beta3-cells. The regulation of osteopontin, osteocalcin, and BSP expression was mediated via transcriptional mechanism because their promoter activities were altered. Examination of molecules involved in integrin signaling indicated that activator protein-1 (AP-1) and extracellular signal-regulated kinase (Erk) activities were enhanced whereas c-jun N-terminal kinase (JNK) activity was decreased in alpha(v)beta3-cells. The activity of p38 and the levels of focal adhesion kinase (FAK) and vinculin were not altered. Moreover, the adhesions of alpha(v)beta3-cells to type I collagen and fibronectin were inhibited, which was attributed to decreased beta1-integrin levels on cell surface. In conclusion, overexpressing alpha(v)beta3-integrin in osteoblasts stimulated cell proliferation but retarded differentiation, which were derived via altered integrin-matrix interactions, signal transduction, and matrix protein expression.
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PMID:Bone mineralization and osteoblast differentiation are negatively modulated by integrin alpha(v)beta3. 1120 28

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.
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PMID:Alpha2beta1 integrin-specific collagen-mimetic surfaces supporting osteoblastic differentiation. 1516

Nano-fibrous poly(L-lactic acid) (PLLA) scaffolds with interconnected pores were developed under the hypothesis that nano-fibrous scaffolding would mimic a morphological function of collagen fibrils to create a more favorable microenvironment for cells versus solid-walled scaffolds. In this study, an in vitro system was used to examine biological properties of the nano-fibrous scaffolds compared with those of solid-walled scaffolds for their potential use in bone tissue engineering. Biomineralization was enhanced substantially on the nano-fibrous scaffolds compared to solid-walled scaffolds, and this was confirmed by von Kossa staining, measurement of calcium contents, and transmission electron microscopy. In support of this finding, osteoblasts cultured on the nano-fibrous scaffolds exhibited higher alkaline phosphatase activity and an earlier and enhanced expression of the osteoblast phenotype versus solid-walled scaffolds. Most notable were the increases in runx2 protein and in bone sialoprotein mRNA in cells cultured on nano-fibrous scaffolds versus solid-walled scaffolds. At the day 1 of culture, alpha2 and beta1 integrins as well as alphav and beta3 integrins were highly expressed on the surface of cells seeded on nano-fibrous scaffolds, and linked to this were higher levels of phospho-Paxillin and phospho-FAK in cell lysates. In contrast, cells seeded on solid-walled scaffolds expressed significantly lower levels of these integrins, phospho-Paxillin, and phospho-FAK. To further examine the role of nano-fibrous architecture, we inhibited the formation of collagen fibrils by adding 3,4-dehydroproline to cultures and then assayed cells for expression of alpha2 integrin. Cells seeded on nano-fibrous scaffolds sustained expression of alpha2 integrin in the presence of dehydroproline, while suppression of alpha2 integrin was evident in cells seeded on solid-walled scaffolds. These results provide initial evidence that synthetic nano fibers may exhibit certain properties that are comparable to natural collagen fibers, and thus, the nano-fibrous architecture may serve as a superior scaffolding versus solid-walled architecture for promoting osteoblast differentiation and biomineralization.
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PMID:Nano-fibrous scaffolding promotes osteoblast differentiation and biomineralization. 1685 61

Human mesenchymal stem cell (hMSC) differentiation into osteoblasts and the signaling events involved are poorly understood. We recently established that contact with specific extracellular matrix (ECM) proteins, in particular laminin-5, is sufficient to induce an osteogenic phenotype in hMSC through an extracellular signal-related kinase (ERK)-dependent pathway. Activation of ERK 1/2 by laminin-5 induces phosphorylation of the runx2/cbfa-1 transcription factor that controls osteogenic gene expression. We hypothesized that focal adhesion kinase (FAK) mediated signaling pathways supply a link between cell surface integrin-ECM binding and activation of ERK 1/2, and that laminin-5 promotes its osteogenic effects through this pathway. To test this hypothesis, we plated hMSC on a laminin-5 matrix in the presence or absence of FAK-specific small inhibitory RNAs (siRNA), and assayed for phosphorylation of runx2/cbfa-1 as well as expression of established osteogenic differentiation markers (bone sialoprotein, osteocalcin, alkaline phosphatase, calcium deposition, and mineral:matrix ratio). We found that siRNA treatment reduced total endogenous FAK protein by approximately 40%, and reduced FAK phosphorylation on Y397 by approximately 33% in cells plated on laminin-5 for 30 min. SiRNA treated cells exhibited a decrease in ERK 1/2 phosphorylation after 1 h, and reduced serine/threonine phosphorylation of Runx2/Cbfa-1 after 8 days. Finally, FAK inhibition blocked osteogenic differentiation of hMSC, as assessed by lowered expression of osteogenic genes (RT-PCR), decreased alkaline phosphatase activity, greatly reduced calcium deposition, and a lower mineral:matrix ratio after 28 days in culture. These results establish FAK as an important mediator of laminin-5-induced osteogenic differentiation of hMSC.
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PMID:Activation of FAK is necessary for the osteogenic differentiation of human mesenchymal stem cells on laminin-5. 1692 79

The intracellular signaling events controlling human mesenchymal stem cells (hMSC) differentiation into osteoblasts are not entirely understood. We recently demonstrated that contact with extracellular matrix (ECM) proteins is sufficient to induce osteogenic differentiation of hMSC through an ERK-dependent pathway. We hypothesized that FAK signaling pathways provide a link between activation of ERK1/2 by ECM, and stimulate subsequent phosphorylation of the Runx2/Cbfa-1 transcription factor that controls osteogenic gene expression. We plated hMSC on purified collagen I (COLL-I) and vitronectin (VN) in the presence or absence of FAK-specific siRNA, and assayed for phosphorylation of Runx2/Cbfa-1 as well as expression of established osteogenic differentiation markers (bone sialoprotein-2, osteocalcin, alkaline phosphatase, calcium deposition, and spectroscopically determined mineral:matrix ratio). We found that siRNA treatment reduced FAK mRNA levels by >40% and decreased ECM-mediated phosphorylation of FAK Y397 and ERK1/2. Serine phosphorylation of Runx2/Cbfa-1 was significantly reduced after 8 days in treated cells. Finally, FAK inhibition blocked osterix transcriptional activity and the osteogenic differentiation of hMSC, as assessed by lowered expression of osteogenic genes (RT-PCR), decreased alkaline phosphatase activity, greatly reduced calcium deposition, and a lower mineral:matrix ratio after 28 days in culture. These results suggest that FAK signaling plays an important role in regulating ECM-induced osteogenic differentiation of hMSC.
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PMID:Focal adhesion kinase signaling pathways regulate the osteogenic differentiation of human mesenchymal stem cells. 1708 17

The overall mechanisms governing the role of laminins during osteogenic differentiation of human mesenchymal stem cells (hMSC) are poorly understood. We previously reported that laminin-332 induces an osteogenic phenotype in hMSC and does so through a focal adhesion kinase (FAK) and extracellular signal-related kinase (ERK) dependent pathway. We hypothesized that this is a result of integrin-ECM binding, and that it occurs via the known alpha3 LG3 integrin binding domain of laminin-332. To test this hypothesis we cultured hMSC on several different globular domains of laminin-332. hMSC adhered best to the LG3 domain, and this adhesion maximally activated FAK and ERK within 120 min. Prolonged culturing (8 or 16 days) of hMSC on LG3 led to activation of the osteogenic transcription factor Runx2 and expression of key osteogenic markers (osterix, bone sialoprotein 2, osteocalcin, alkaline phosphatase, extracellular calcium) in hMSC. LG3 domain binding did not increase matrix mineralization, demonstrating that the LG3 domain alone is not sufficient to induce complete osteogenic differentiation in vitro. We conclude that the LG3 domain mediates attachment of hMSC to laminin-332 and that this adhesion recapitulates most, but not all, of the osteogenic differentiation associated with laminin-5 binding to hMSC.
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PMID:Dissection of the osteogenic effects of laminin-332 utilizing specific LG domains: LG3 induces osteogenic differentiation, but not mineralization. 1820 71

The mammalian growth plate is a dynamic structure rich in extracellular matrix (ECM). Interactions of growth plate chondrocytes with ECM proteins regulate cell behavior. In this study, we compared chondrocyte adhesion and spreading dynamics on fibronectin (FN) and bone sialoprotein (BSP). Chondrocyte adhesion and spreading were also compared with fibroblasts to analyze potential cell-type-specific effects. Chondrocyte adhesion to BSP is independent of posttranslational modifications but is dependent on the RGD sequence in BSP. Whereas chondrocytes and fibroblasts adhered at similar levels on FN and BSP, cells displayed more actin-dependent spread on FN despite a 16x molar excess of BSP adsorbed to plastic. To identify intracellular mediators responsible for this difference in spreading, we investigated focal adhesion kinase (FAK)-Src and Rho-Rho kinase (ROCK) signaling. Although activated FAK localized to the vertices of adhered chondrocytes, levels of FAK activation did not correlate with the extent of spreading. Furthermore, Src inhibition reduced chondrocyte spreading on both FN and BSP, suggesting that FAK-Src signaling is not responsible for less cell spreading on BSP. In contrast, inhibition of Rho and ROCK in chondrocytes increased cell spreading on BSP and membrane protrusiveness on FN but did not affect cell adhesion. In fibroblasts, Rho inhibition increased fibroblast spreading on BSP while ROCK inhibition changed membrane protrusiveness of FN and BSP. In summary, we identify a novel role for Rho-ROCK signaling in regulating chondrocyte spreading and demonstrate both cell- and matrix molecule-specific mechanisms controlling cell spreading.
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PMID:Rho-ROCK signaling differentially regulates chondrocyte spreading on fibronectin and bone sialoprotein. 1846 28


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