Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BRK-3 is a vertebrate type II receptor for BMP-4 distantly related to invertebrate type II receptors for BMP-2/BMP-4/dpp, such as daf-4 and punt. BRK-3 has a long carboxy-terminal sequence following intracellular kinase domain and is capable of forming a high-affinity complex with a type I receptor, BRK-2. To examine the role of BRK-2 + BRK-3 receptor complex in BMP signaling during early embryogenesis, the dominant-negative form of BRK-3 was ectopically expressed in the Xenopus embryos. A secondary body axis expressing the Sonic hedgehog and N-CAM genes is induced by injecting mRNA encoding truncated form of BRK-3 into ventral marginal region, implicating the BMP signaling in axial mesoderm induction. Formation of the secondary axis depends on whether the deletion extends into the kinase domain, not into the carboxy-terminal tail, suggesting that the kinase domain, but not the tail region, is essential for BMP signaling.
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PMID:Truncated type II receptor for BMP-4 induces secondary axial structures in Xenopus embryos. 748 98

The bone morphogenetic proteins (BMPs) are a group of transforming growth factor beta (TGF-beta)-related factors whose only receptor identified to date is the product of the daf-4 gene from Caenorhabditis elegans. Mouse embryonic NIH 3T3 fibroblasts display high-affinity 125I-BMP-4 binding sites. Binding assays are not possible with the isoform 125I-BMP-2 unless the positively charged N-terminal sequence is removed to create a modified BMP-2, 125I-DR-BMP-2. Cross-competition experiments reveal that BMP-2 and BMP-4 interact with the same binding sites. Affinity cross-linking assays show that both BMPs interact with cell surface proteins corresponding in size to the type I (57- to 62-kDa) and type II (75- to 82-kDa) receptor components for TGF-beta and activin. Using a PCR approach, we have cloned a cDNA from NIH 3T3 cells which encodes a novel member of the transmembrane serine/threonine kinase family most closely resembling the cloned type I receptors for TGF-beta and activin. Transient expression of this receptor in COS-7 cells leads to an increase in specific 125I-BMP-4 binding and the appearance of a major affinity-labeled product of approximately 64 kDa that can be labeled by either tracer. This receptor has been named BRK-1 in recognition of its ability to bind BMP-2 and BMP-4 and its receptor kinase structure. Although BRK-1 does not require cotransfection of a type II receptor in order to bind ligand in COS cells, complex formation between BRK-1 and the BMP type II receptor DAF-4 can be demonstrated when the two receptors are coexpressed, affinity labeled, and immunoprecipitated with antibodies to either receptor subunit. We conclude that BRK-1 is a putative BMP type I receptor capable of interacting with a known type II receptor for BMPs.
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PMID:Characterization and cloning of a receptor for BMP-2 and BMP-4 from NIH 3T3 cells. 806 29

To examine the role of BMP signaling during limb pattern formation, we isolated chicken cDNAs encoding type I (BRK-1 and BRK-2) and type II (BRK-3) receptors for bone morphogenetic proteins. BRK-2 and BRK-3, which constitute dual-affinity signaling receptor complexes for BMPs, are co-expressed in condensing precartilaginous cells, while BRK-1 is weakly expressed in the limb mesenchyme. BRK-3 is also expressed in the apical ectodermal ridge and interdigital limb mesenchyme. BRK-2 is intensely expressed in the posterior-distal region of the limb bud. During digit duplication by implanting Sonic hedgehog-producing cells, BRK-2 expression is induced anteriorly in the new digit forming region as observed for BMP-2 and BMP-7 expression in the limb bud. Dominant-negative effects on BMP signaling were obtained by over-expressing kinase domain-deficient forms of the receptors. Chondrogenesis of limb mesenchymal cells is markedly inhibited by dominant-negative BRK-2 and BRK-3, but not by BRK-1. Although the bone pattern was not disturbed by expressing individual dominant-negative BRK independently, preferential distal and posterior limb truncations resulted from co-expressing the dominant-negative forms of BRK-2 and BRK-3 in the whole limb bud, thus providing evidence that BMPs are essential morphogenetic signals for limb bone patterning.
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PMID:BMP signaling during bone pattern determination in the developing limb. 895 Oct 71

Signals from bone morphogenetic protein receptors (BMPRs) and cell adhesion to type I collagen are both important for osteoblastic differentiation and functions. BMP signals are mediated mostly by Smad and collagen signals are transduced by integrins to activate focal adhesion kinase (FAK) and its downstream molecules. This study was undertaken to clarify how extracellular matrix collagen signals converge with BMP actions. We show that integrin activation by collagen was involved in BMP signals because disruption of either collagen synthesis or collagen-alpha2beta1-integrin binding inhibited the stimulatory effect of BMP-2 on osteoblastic MC3T3-E1 cells. Downstream signals of collagen-integrin might be FAK-Ras-extracellular signal-regulated kinase (ERK) in osteoblastic cells. We further show that Ras-ERK signals enhanced the transcriptional activity of Smad1 in response to BMP in these cells transiently transfected with expression plasmids for a constitutively active mutant RasV12, a dominant negative mutant RasN17, and an ERK phosphatase CL100. Ras-ERK signals did not augment the transcriptional activity of Smad3 in response to transforming growth factor beta (TGF-beta) receptor activation but that of Smad1 in response to BMPR activation as examined in COS-1 cells. These observations suggest that the Ras-ERK pathway downstream of integrin-FAK is involved in Smad1 signals activated by BMP and provide a possible mechanism for cooperation between intracellular signals activated by integrin and BMPRs in osteoblastic cells.
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PMID:Stimulation of Smad1 transcriptional activity by Ras-extracellular signal-regulated kinase pathway: a possible mechanism for collagen-dependent osteoblastic differentiation. 1181 54

The bone morphogenetic proteins (BMPs) are potent osteoinductive factors that accelerate osteoblast maturation, accompanied by increased cell-substrate adhesion. BMP-2 treatment of osteoblastic cells increases phosphorylation of the cytoplasmic BMP-2 signaling molecules, Smad1 and Smad5. We have previously reported that BMP-2 treatment increase cytoskeletal organization of human trabecular bone-derived osteoblast-like cells (osteoblasts), which is also accompanied by an activation of the focal adhesion kinase p125(FAK). We report here that activation of p125(FAK) occurs with the same kinetics as the phosphorylation of Smad1, suggesting that BMP-2 initiates cross-talk between Smad signaling and the adhesion-mediated signaling pathway. As an adjunct to these effects, we examined activation of mitogen-activated protein (MAP) kinase family members in response to focal adhesion contact formation. Although phosphorylated forms of all three kinases were apparent, only SAPK2alpha/p38 (p38) was activated in response to BMP-2 treatment. Inhibition of p38 kinase activity suppressed BMP-2 induced Smad1 phosphorylation, as well as its translocation to the nucleus, suggesting the integration of p38 activation with Smad1 signaling. Finally, inhibition of p38 in osteoblasts also led to the complete abrogation of BMP-2 induced osteocalcin gene expression and matrix mineralization. These findings suggest that BMP-2 must activate p38 in order to mediate osteogenic differentiation and maturation.
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PMID:Activation of p38 and Smads mediates BMP-2 effects on human trabecular bone-derived osteoblasts. 1459 20

Bone morphogenetic protein (BMP)-2, a multifunctional member of the transforming growth factor (TGF)-beta superfamily with powerful osteoinductive effects, has various biological activities in a variety of cells. We observed that BMP-2 inhibits cell proliferation in the androgen-dependent human prostate cancer cell line, LNCaP. To investigate the mechanism of inhibition of androgen-dependent growth by BMP-2, we compared the gene expression in LNCaP cells treated with dihydrotestosterone (DHT) to that of LNCaP cells treated with DHT and BMP-2, using DNA microarray analysis. Of 8,400 human genes on the gene chip, 38 genes were up-regulated by >2.0-fold and 48 genes were down-regulated by <0.5-fold by treatment with BMP-2. These genes were involved in a variety of cellular functions, including signal transduction, transcription regulation, enzymes, transporters, structural molecules and translation. RT-PCR analysis showed that CH1CL and BMX were up-regulated and DACH1 and WNT5A were down-regulated by treatment with BMP-2. Furthermore, we detected an increase of WNT5A protein in the medium by DHT and inhibition of the increase by BMP-2. In the present study, we identified several BMP-2-responsive genes in LNCaP cells. Further studies of the roles of these genes may clarify the mechanisms underlying the inhibition of cell proliferation by BMP-2 and identify better approaches for the prevention and treatment of prostate cancer.
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PMID:Alteration of gene expression in response to bone morphogenetic protein-2 in androgen-dependent human prostate cancer LNCaP cells. 1639 28

Cell migration is essential for both organogenesis and tumor progression. Bone morphogenetic proteins (BMPs) are reported to be critical for not only bone formation but also tumor invasion. Here, we found that treatment with recombinant human BMP-2 (rhBMP-2) enhanced the haptotactic response of murine osteoblastic MC3T3-E1 and osteosarcoma Dunn cells to various extracellular matrix (ECM) components, including fibronectin, type I collagen, and laminin-1. Function-blocking antibody against integrin alpha5beta1 partially inhibited haptotaxis to fibronectin, suggesting that the response was propagated via these integrins. rhBMP-2 slightly increased the expression level of integrin beta1, and enhanced the speed of cell spreading on fibronectin, focal adhesion formation and phosphorylation of focal adhesion kinase (FAK) at Tyr397. By means of sucrose gradient flotation, incorporation of integrin beta1 in fractions of detergent (CHAPS) resistant membrane was increased when the cells were treated with rhBMP-2. Further, treatment with methyl-beta-cyclodextrin to deplete membrane cholesterol abrogated the effect of rhBMP-2 on haptotaxis, and exogenously added cholesterol reversed this inhibitory effect. Collectively, these results provide insights into the mechanism by which BMP signaling enhances cell migration by modulating fibronectin-integrin beta1 signaling via cholesterol enriched membrane microdomains, lipid rafts.
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PMID:Bone morphogenetic protein-2 promotes the haptotactic migration of murine osteoblastic and osteosarcoma cells by enhancing incorporation of integrin beta1 into lipid rafts. 1702 72

In the current study, we have examined the efficacy of a Src/Abl kinase inhibitor SKI-606 (Bosutinib) for its effect on prostate cancer growth and skeletal metastasis. Treatment of highly invasive human prostate cancer cells PC-3 and DU-145 with different doses of SKI-606 decreased Src activation, cell proliferation, migration, and invasion as determined by Matrigel Boyden chamber invasion assay. For in vivo studies, PC-3 cells were inoculated through s.c. or i.t. route into male BALB/c nu/nu or Fox Chase severe combined immunodeficient mice, respectively. Experimental animals treated with SKI-606 developed tumors of a significantly smaller volume and a significant decrease (50%) in experimental skeletal lesion area. A marked increase (32%) in bone volume to tumor volume ratio was also seen by micro-computed tomography analysis of tibias from control and experimental groups of animals. Western blot analysis showed the ability of SKI-606 to significantly decrease the phosphorylation of signaling molecules (AKT, mitogen-activated protein kinase, focal adhesion kinase) and the expression of tumor progression-associated genes uPAR, MMP-2, MMP-9, N-cadherin, fibronectin, BMP-2 (bone morphogenetic protein 2), BMP-6 (bone morphogenetic protein 6), IL-8 (interleukin 8), and TGF-beta (transforming growth factor beta) in prostate cancer cells. SKI-606 is currently in clinical trials for breast cancer and chronic myelogenous leukemia. Results from these studies provide convincing evidence for evaluating its efficacy in prostate cancer patients.
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PMID:SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis. 2042 91

Mesenchymal stem cell differentiation of osteoblasts is triggered by a series of signaling processes including integrin and bone morphogenetic protein (BMP), which therefore act in a cooperative manner. The aim of this study was to analyze whether these processes can be remodeled in an artificial poly-(L)-lactide acid (PLLA) based nanofiber scaffold. Matrices composed of PLLA-collagen type I or BMP-2 incorporated PLLA-collagen type I were seeded with human mesenchymal stem cells (hMSC) and cultivated over a period of 22 days, either under growth or osteoinductive conditions. During the course of culture, gene expression of alkaline phosphatase (ALP), osteocalcin (OC) and collagen I (COL-I) as well as Smad5 and focal adhesion kinase (FAK), two signal transduction molecules involved in BMP-2 or integrin signaling were analyzed. Furthermore, calcium and collagen I deposition, as well as cell densities and proliferation, were determined using fluorescence microscopy. The incorporation of BMP-2 into PLLA-collagen type I nanofibers resulted in a decrease in diameter as well as pore sizes of the scaffold. Mesenchymal stem cells showed better adherence and a reduced proliferation on BMP-containing scaffolds. This was accompanied by an increase in gene expression of ALP, OC and COL-I. Furthermore the presence of BMP-2 resulted in an upregulation of FAK, while collagen had an impact on the gene expression of Smad5. Therefore these different strategies can be combined in order to enhance the osteoblast differentiation of hMSC on PLLA based nanofiber scaffold. By doing this, different signal transduction pathways seem to be up regulated.
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PMID:Functionalisation of PLLA nanofiber scaffolds using a possible cooperative effect between collagen type I and BMP-2: impact on growth and osteogenic differentiation of human mesenchymal stem cells. 2160 39

Distal outgrowth and maturation of mesenchymalized endocardial cushions are critical morphogenetic events during post-EMT atrioventricular (AV) valvuloseptal morphogenesis. We explored the role of BMP-2 in the regulation of valvulogenic extracellular matrix (ECM) components, versican and hyaluronan (HA), and cell migration during post-EMT AV cushion distal outgrowth/expansion. We observed intense staining of versican and HA in AV cushion mesenchyme from the early cushion expansion stage, Hamburger and Hamilton (HH) stage-17 to the cushion maturation stage, HH stage-29 in the chick. Based on this expression pattern we examined the role of BMP-2 in regulating versican and HA using 3D AV cushion mesenchymal cell (CMC) aggregate cultures on hydrated collagen gels. BMP-2 induced versican expression and HA deposition as well as mRNA expression of versican and Has2 by CMCs in a dose dependent manner. Noggin, an antagonist of BMP, abolished BMP-2-induced versican and HA as well as mRNA expression of versican and Has2. We further examined whether BMP-2-promoted cell migration was associated with expression of versican and HA. BMP-2- promoted cell migration was significantly impaired by treatments with versican siRNA and HA oligomer. In conclusion, we provide evidence that BMP-2 induces expression of versican and HA by AV CMCs and that these ECM components contribute to BMP-2-induced CMC migration, indicating critical roles for BMP-2 in distal outgrowth/expansion of mesenchymalized AV cushions.
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PMID:BMP-2 induces versican and hyaluronan that contribute to post-EMT AV cushion cell migration. 2414 33


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