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)

Yeast two-hybrid screening was used to explore novel proteins that interact with a breast tumor or metastasis suppressor, SYK (spleen tyrosine kinase). The screening yielded NHERF (Na+/H+ exchanger regulatory factor, also known as NHERF1 or EBP-50) that binds to the interdomain B of SYK. NHERF is an estrogen-responsive gene that encodes an inhibitory factor for epithelial Na+/H+ exchanger isoform 3 (NHE3). We found intragenic mutation of the NHERF gene accompanied by loss of heterzygosity (LOH) in approximately 3% (3/85) of breast cancer cell lines and primary breast tumors. Mutations occurred at the conserved PDZ domains at NHERF NH2-terminus that bound to SYK, or at its COOH-terminus motif that binds to MERLIN, the product of Neurofibromatosis 2 (NF2) tumor suppressor gene. NHERF tumorigenic mutations decreased or abolished its interaction with SYK or MERLIN, suggesting a pathway link among these three molecules that may play a critical role in mammary neoplastic progression. Primary breast tumors with LOH at the NHERF locus had clinical presentations of higher aggressiveness, indicating that deregulated NHERF signaling may be associated with disease progression. Moreover, the LOH was inversely correlated with SYK promoter methylation, suggesting that NHERF and SYK may transduce a common suppressive signal. Taken together, the results indicated NHERF to be a candidate tumor suppressor gene in human breast carcinoma that may be interconnected to the SYK and MERLIN suppressors.
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PMID:NHERF (Na+/H+ exchanger regulatory factor) gene mutations in human breast cancer. 1546 53

The clinical course of chronic lymphocytic leukemia (CLL) differs significantly between patients with mutated (M-CLL) and unmutated (U-CLL) immunoglobulin (Ig) variable heavy-chain (V(H)) genes, implying a role for B-cell receptor (BCR) signaling in the pathogenesis of this disease. We have now investigated activation of downstream BCR signaling pathways in U-CLL and M-CLL B cells using soluble anti-IgM (sol-IgM) and immobilized anti-IgM (imm-IgM) antibodies as models for antigenic stimulation. Ligation of the BCR with sol-IgM induced incomplete responses in both CLL subsets, resembling the pattern described for tolerant B cells. This response was characterized by transient phosphorylation of extracellular signal-related kinase (ERK) and Akt (protein kinase B [PKB]), lack of activation of c-JUN NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and variable activation of phospholipase Cgamma2 (PLCgamma2) and nuclear factor-kappaB (NF-kappaB). Stimulation with imm-IgM elicited a more complete BCR signal and significantly prolonged phosphorylation of ERK and Akt, indicating persistent or repetitive BCR signaling. Moreover, this type of stimulation increased the levels of the antiapoptotic protein myeloid cell leukemia-1 (Mcl-1) and protected from chemotherapy-induced apoptosis, whereas induction of apoptosis and down-regulation of Mcl-1 was observed following stimulation with sol-IgM. These data demonstrate that only sustained BCR signaling can promote survival of CLL B cells and indicate that the main difference between CLL with mutated and unmutated V(H) genes may reside in the availability of such stimulation.
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PMID:Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells. 1572 30

Activated signaling proteins regulate diverse processes, including the differentiation of the pancreatic islet cells during ontogeny. Here we uncover the in vivo phosphorylation status of major growth factor-activated signaling proteins in normal adult mice and during pancreatic islet regeneration. We report elevated phospho-mitogen-activated protein kinase (phospho-MAPK), phospho-c-Jun-NH2-terminal kinase (phospho-JNK), and phospho-p38 MAPK expression during pancreatic regeneration. Immunoblotting experiments demonstrated elevated phosphorylation of p52 Src-homology/collagen (SHC) in the ductal network as well, substantiating the activation of this pathway. Furthermore, protein kinase B (PKB/Akt), a key signaling protein in the anti-apoptotic pathway, was phosphorylated to a greater extent in the ductal network from regenerating pancreas. We observed fibroblast growht factor (FGF)10 and platelet-derived growth factor (PDGF)AA expression in embryonic as well as regenerating adult pancreas. Epidermal growth factor (EGF) and PDGFAA stimulated MAPK and Akt phosphorylation, while FGF10 stimulated MAPK but not Akt phosphorylation in a time-dependent manner in freshly isolated cells from the adult ductal network. These data suggest that a heightened level of expression and stimulation of key signaling proteins underlie the expansion and differentiation processes that support pancreatic ontogeny and regeneration.
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PMID:Growth factor-induced signaling of the pancreatic epithelium. 1581 26

FIP200 is a novel protein inhibitor for focal adhesion kinase (FAK), which binds to FAK directly and inhibits its kinase activity and associated cellular functions, such as cell adhesion, spreading, and motility in fibroblasts. Here we show that FIP200 inhibits G1-S phase progression, proliferation, and clonogenic survival in human breast cancer cells. Consistent with the G1 arrest induced by FIP200, we found that FIP200 increased p21 and decreased cyclin D1 protein levels in breast cancer cells. In addition, FIP200 significantly induced p21 promoter activity in MCF-7 cells and this response was abolished upon deletion of p53 binding sites within p21 promoter. Furthermore, we found that FIP200 could interact with exogenous and endogenous p53 protein and significantly increase its half-life compared with the control cells. We also found that the NH2-terminal 154 residues of FIP200 were sufficient to mediate p53 interaction and G1 arrest in cells. The increase in p53 half-life correlated with the increased phosphorylation at Ser15 and decreased proteasomal degradation via ubiquitin and Hdm2-independent mechanism. Stabilization of p53 by FIP200 could be partially reversed by NQO1 inhibitor, dicoumarol. In contrast to p53, FIP200 decreased cyclin D1 protein half-life by promoting proteasome-dependent degradation of cyclin D1. In summary, our results suggest that FIP200 increases p21 protein levels via stabilization of its upstream regulator p53 and decreases cyclin D1 protein by promoting its degradation. Both effects are critical for FIP200-induced G1 arrest and may contribute to the putative antitumor activities of FIP200 in breast cancer.
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PMID:Mechanism of cell cycle regulation by FIP200 in human breast cancer cells. 1606 48

Leukocyte transmigration can be affected by shear stress; however, the mechanisms by which shear stress modulates transmigration are unknown. We found that adhesion of eosinophils or an eosinophilic cell line to intereukin 4-stimulated endothelial cells led to a shear-dependent increase in endothelial cell intracellular calcium and increased phosphorylation of extracellular signal-regulated kinase (ERK) 2, but not c-Jun NH2-terminal kinase or p38 mitogen-activated protein kinase. Latex beads coated with antibodies were used to characterize the role of specific endothelial cell surface molecules in initiating signaling under shear conditions. We found that ligation of either vascular cell adhesion molecule-1 or E-selectin, but not major histocompatibility complex class I, induced a shear-dependent increase in ERK2 phosphorylation in cytokine-stimulated endothelial cells. Disassembly of the actin cytoskeleton with latrunculin A prevented ERK2 phosphorylation after adhesion under flow conditions, supporting a role for the cytoskeleton in mechano-sensing. Rapid phosphorylation of focal adhesion kinase and paxillin occurred under identical conditions, suggesting that focal adhesions were also involved in mechanotransduction. Finally, we found that Rho-associated protein kinase and calpain were both critical in the subsequent transendothelial migration of eosinophils under flow conditions. These data suggest that ligation of leukocyte adhesion molecules under flow conditions leads to mechanotransduction in endothelial cells, which can regulate subsequent leukocyte trafficking.
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PMID:Eosinophil adhesion under flow conditions activates mechanosensitive signaling pathways in human endothelial cells. 1617 63

Metastasis is a significant event in cancer progression and continues to pose the greatest challenge for a cancer cure. Defining genes that control metastasis in vivo may provide new targets for intervening in this process with profound therapeutic implications. Melanoma differentiation associated gene-9 (mda-9) was initially identified by subtraction hybridization as a novel gene displaying biphasic expression during terminal differentiation in human melanoma cells. Mda-9, also known as syntenin, is a PDZ-domain protein overexpressed in many types of human cancers, where it is believed to function in tumor progression. However, a functional role of mda-9/syntenin in tumor growth and metastasis and the signaling pathways involved in mediating these biological activities remain to be defined. Evidence is now provided, using weakly and highly metastatic isogenic melanoma variants, that mda-9/syntenin regulates metastasis. Expression of mda-9/syntenin correlates with advanced stages of melanoma progression. Regulating mda-9/syntenin expression using a replication-incompetent adenovirus expressing either sense or antisense mda-9/syntenin modifies the transformed phenotype and alters metastatic ability in immortal human melanocytes and metastatic melanoma cells in vitro and in vivo in newborn rats. A direct relationship is observed between mda-9/syntenin expression and increased phosphorylation of focal adhesion kinase, c-Jun-NH2-kinase, and p38. This study provides the first direct link between mda-9/syntenin expression and tumor cell dissemination in vivo and indicates that mda-9/syntenin expression activates specific signal transduction pathways, which may regulate melanoma tumor progression. Based on its ability to directly alter metastasis, mda-9/syntenin provides a promising new focus for melanoma cancer research with potential therapeutic applications for metastatic diseases.
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PMID:mda-9/Syntenin: a positive regulator of melanoma metastasis. 3157 35

Glycine-extended gastrin (G-Gly) is produced by colon cancers and has growth promoting and anti-apoptotic effects in the colonic epithelium. We have examined the anti-apoptotic effects of G-Gly and the signal transduction pathways involved. G-Gly stimulated HT-29 cell proliferation in a concentration dependent manner and inhibited serum-starvation and celecoxib-induced apoptosis. Inhibition of signalling via c-Jun NH2-terminal kinase (JNK) with SP600125 or PI3-kinase/Akt with LY294002 abolished the effects of G-Gly. G-Gly significantly increased phosphorylation of both JNK and Akt. The JAK2 inhibitor AG490 abolished the anti-apoptotic effect of G-Gly and inhibited phosphorylation of Akt but not of JNK. G-Gly stimulated tyrosine phosphorylation of JAK2. G-Gly-increased activation of AP-1 was JNK-dependant and activation of STAT3 was JAK2-dependant. We conclude that G-Gly promotes growth and inhibits apoptosis in colon cancer cells. These effects are mediated via the JAK2, PI3-kinase/Akt and JNK pathways. Activation of JAK2 is upstream of Akt but not of JNK.
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PMID:Glycine-extended gastrin inhibits apoptosis in colon cancer cells via separate activation of Akt and JNK pathways. 1644 4

The search for effective chemopreventive compounds is a major challenge facing research into preventing the progression of cancer cells. The naturally occurring polyphenol antioxidants look very promising, but their mechanism of action still remains poorly understood. Here, we show that 2-(3,4-dihydroxyphenyl)ethanol (DPE), a phenol antioxidant derived from olive oil, induces growth arrest and apoptosis in human colon carcinoma HT-29 cells. The mechanisms involve prolonged stress of the endoplasmic reticulum (ER) leading to the activation of the two main branches of the unfolded protein response (UPR), including the Ire1/XBP-1/GRP78/Bip and PERK/eIF2alpha arms. DPE treatment led to overexpression of the pro-apoptotic factor CHOP/GADD153 and persistent activation of the Jun-NH2-terminal kinase/activator protein-1 signaling pathway. DPE concomitantly modulated the extracellular signal-regulated kinase 1/2 and Akt/PKB pro-survival factors by altering their phosphorylation status as well as inhibiting tumor necrosis factor-alpha-induced nuclear factor-kappaB activation by inactivating the phosphorylation of nuclear factor inhibitor-kappaB kinase. These findings prompted us to investigate the possible involvement of phosphatases in DPE-mediated action. Using phosphatase inhibitors and RNA interference to silence the Ser/Thr phosphatase 2A (PP2A) prevented DPE-induced cell death. These findings demonstrate that DPE specifically activates PP2A, which plays a key initiating role in various pathways that lead to apoptosis in colon cancer cells.
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PMID:Dihydroxyphenylethanol induces apoptosis by activating serine/threonine protein phosphatase PP2A and promotes the endoplasmic reticulum stress response in human colon carcinoma cells. 1652 88

Protease-activated receptor 2 (PAR2) has been implicated in the pathogenesis of airway inflammation. We report that epithelial PAR2 stimulation with trypsin (0.05-1 U/ml) or an agonist peptide (SLIGKV-NH2, 1-100 microM) for 0.5-3 h dose- and time-dependently enhanced neutrophil adhesion to alveolar type II epithelial cells (A549 cells) and that this stimulation also induced the formation of epithelial actin filaments. Both responses in neutrophil adhesion and epithelial actin reorganization were reduced by a Rho inhibitor, mevastatin and by a Rho-associated kinase (ROCK) inhibitor, Y-27632 ((R)-(+)-trans-N-(4-Pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide). Neutrophil adherence was also inhibited by an inhibitor of actin polymerization, cytochalasin D and a tyrosine kinase inhibitor, genistein. Further, the PAR2-mediated tyrosine phosphorylation of focal adhesion kinase (FAK), a major cytoskeleton protein, was detected, and this response was inhibited by mevastatin or Y-27632. These results suggest that PAR2 stimulation of alveolar epithelial cells enhances neutrophil adhesion presumably at least in part through Rho/ROCK signal-mediated actin cytoskeleton reorganization associated with the tyrosine phosphorylation of FAK.
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PMID:Involvement of Rho signaling in PAR2-mediated regulation of neutrophil adhesion to lung epithelial cells. 1656 23

Many cytokines increase their receptor affinity for Janus kinases (JAKs). Activated JAK binds to signal transducers and activators of transcription, insulin receptor substrates (IRSs), and Shc. Intriguingly, insulin acting through its own receptor kinase also activates JAK2. However, the impact of such activation on insulin action remains unknown. To determine the contribution of JAK2 to insulin signaling, we transfected L6 myotubes with siRNA against JAK2 (siJAK2), reducing JAK2 protein expression by 75%. Insulin-dependent phosphorylation of IRS1/2 and Shc was not affected by siJAK2, but insulin-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) extracellular signal-related kinase, p38, and Jun NH2-terminal kinase and their respective upstream kinases MKK1/2, MKK3/6, and MKK4/7 was significantly lowered when JAK2 was depleted, correlating with a significant drop in insulin-mediated cell proliferation. These effects were reproduced by the JAK2 inhibitor AG490. Conversely, insulin-stimulated Akt phosphorylation, glucose uptake, and GLUT4 translocation were not affected by siJAK2. Interestingly, in two insulin-resistant states, siJAK2 led to partial restoration of Akt phosphorylation and glucose uptake stimulation but not of the MAPK pathway. These results suggest that JAK2 may depress the Akt to glucose uptake signaling axis selectively in insulin-resistant states. Inhibition of JAK2 may be a useful strategy to relieve insulin resistance of metabolic outcomes.
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PMID:Opposite effect of JAK2 on insulin-dependent activation of mitogen-activated protein kinases and Akt in muscle cells: possible target to ameliorate insulin resistance. 1656 15


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