Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein-tyrosine-phosphatases (PTPs), in conjunction with protein-tyrosine kinases, play essential regulatory roles in diverse cellular activities by modulating the phosphorylation state of target proteins. Leukocyte common antigen-related (LAR) protein is a widely expressed receptor-type protein-tyrosine-phosphatase that is implicated in the regulation of intracellular signaling triggered by both cell adhesion and peptide growth factors. The gene for LAR is localized to human chromosome 1p32, a region frequently deleted in tumors of neuroectodermal origin, including neuroblastoma, pheochromocytoma, and medullary thyroid carcinoma. On the other hand, the RET gene codes for a transmembrane tyrosine kinase and is responsible for the development of multiple endocrine neoplasia (MEN) 2A and 2B. To explore the potential role of LAR in RET tyrosine kinase activity and RET-induced signal transduction, we cotransfected LAR and RET with a MEN2A or MEN2B mutation (designated RET-MEN2A or RET-MEN2B) into the NIH 3T3 cell line. Here we show that LAR reduces the constitutive tyrosine autophosphorylation and kinase activity of RET-MEN2A but not RET-MEN2B, accompanying a significant decrease of phosphorylation of phospholipase Cgamma, AKT, and ERK1/2. Interestingly, LAR expression significantly decreased the levels of disulfide-linked RET-MEN2A dimerization. Moreover, reduced oncogenic activity of RET-MEN2A by overexpression of LAR was observed both by an in vitro colony formation assay and by in vivo tumorigenicity in scid mice. These results thus suggest that LAR may contribute to deactivation of the RET-MEN2A mutant protein and reduction of its oncogenic activity in vivo.
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PMID:Differential effects of leukocyte common antigen-related protein on biochemical and biological activities of RET-MEN2A and RET-MEN2B mutant proteins. 1112 8

Big mitogen-activated protein kinase 1 (BMK1) is a new member of mitogen-activated protein kinase (MAPK) family. In the present study, we investigated whether glial cell line-derived neurotrophic factor (GDNF) can induce activation of BMK1 through RET tyrosine kinase. Its activation reached a maximal level at 30 min and continued at least for 120 min after GDNF stimulation. In addition, we detected BMK1 activation in NIH3T3 cells expressing RET with a multiple endocrine neoplasia (MEN) 2A mutation. The level of BMK1 activation markedly decreased by replacement of tyrosine 1062 with phenylalanine (designated Y1062F) in RET, indicating the importance of downstream signaling via tyrosine 1062. However, although both RAS/MAPK and phosphatidylinositol 3-kinase (PI3-K)/AKT signaling pathways are activated via tyrosine 1062, BMK1 activation by GDNF was not significantly impaired by treatment with an MEK1 inhibitor, PD98059, or two distinct PI3-K inhibitors, LY294002 and wortmannin, suggesting that the RAS and PI3-K signaling pathways are not crucial for BMK1 activation by GDNF. Moreover, luciferase reporter assays revealed that RET-MEN2A mutant proteins can activate the MEF2C transcription factor that is known to be a cellular target for BMK1, and that its activation is impaired by the Y1062F mutation or by expression of a dominant negative form of MEK5.
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PMID:Activation of BMK1 via tyrosine 1062 in RET by GDNF and MEN2A mutation. 1123 12

Elevated levels of urokinase plasminogen activator-1 (uPA) and the insulin-like growth factor-I receptor (IGF-IR) are associated with breast cancer recurrence and decreased survival. It is possible that activation of IGF-IR and elevations in uPA are mechanistically linked. Our laboratory recently showed that insulin-like growth factor-I (IGF-I) induces uPA protein and mRNA in the breast cancer cell line MDA-MB-231. We also found that IGF-IR and uPA were commonly overexpressed in primary breast cancers. In this study, we investigated the signal transduction pathway through which IGF-I regulates uPA. Phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p70 kinase were inhibited with LY294002, PD98059, and rapamycin, respectively. Induction of uPA protein by IGF-I was partially inhibited by LY294002 (60% inhibition) or PD98059 (30% inhibition) but not by rapamycin. The production of uPA protein induced by IGF-I was blocked up to 90% by the tyrosine kinase inhibitor herbimycin A. Furthermore, herbimycin A suppressed the phosphorylation of AKT and Erk1/2. Next, we tested the impact of the signal transduction inhibitors on uPA gene expression. Both LY294002 and PD98059 were required to completely inhibit uPA mRNA expression, whereas each drug alone resulted in approximately 50% reduction in uPA expression. Next, using a minimal uPA-luciferase promoter construct containing the binding sites for the AP-1 and Ets transcription factors, we observed that IGF-I stimulated the uPA promoter via these sites. Furthermore, both Ly294002 and PD98059 were necessary to block IGF-I-stimulated uPA-Luc activity. In summary, we conclude that IGF-I requires both phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase-dependent pathways to optimally induce uPA expression. These findings suggest that the development of drugs targeting these pathways may benefit breast cancer patients at a high risk of recurrence, such as those who have primary tumors overexpressing IGF-IR and uPA.
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PMID:Up-regulation of urokinase-type plasminogen activator by insulin-like growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase. 1124 36

MSP is a serum protein belonging to the plasminogen-related kringle domain protein family. In addition to macrophages, epithelial cells are also MSP targets. MSP is a multifunctional factor regulating cell adhesion and motility, growth and survival. MSP mediates its biological activities by activating a transmembrane receptor tyrosine kinase called RON in humans or SKT in mice. MSP can protect epithelial cells from apoptosis by activating two independent signals in the PI3-K/AKT or the MAPK pathway. The MAPK pathway mediates the MSP antiapoptotic effect only if additional signaling pathways are activated through adhesion. This indicates that MSP receptors and integrins, the receptors mediating cell-matrix-dependent adhesion, can collaborate in promotion of cell survival. This adhesion-dependent pathway, which is essential for the MAPK-mediated anti-apoptotic effect, remains to be identified. A hypothesis that Stat3 might represent a key component of the adhesion-induced anti-apoptotic pathway is presented in this review.
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PMID:Anti-apoptotic action of macrophage stimulating protein (MSP). 1138 67

A subset of chromosomal translocations that participate in leukemia involve activated tyrosine kinases. The ets transcription factor, TEL, undergoes translocations with several distinct tyrosine kinases including JAK2. TEL-JAK2 transforms cell lines to factor independence, and constitutive tyrosine kinase activity results in the phosphorylation of several substrates including STAT1, STAT3, and STAT5. In this study we have shown that TEL-JAK2 can constitutively activate the phosphatidylinositol 3'-kinase (PI 3'-kinase) signaling pathway. The regulatory subunit of PI 3'-kinase, p85, associates with TEL-JAK2 in immunoprecipitations, and this was shown to be mediated by the amino-terminal SH2 domain of p85 but independent of a putative p85-binding motif within TEL-JAK2. The scaffolding protein Gab2 can also mediate the association of p85. TEL-JAK2 constitutively phosphorylates the downstream substrate protein kinase B/AKT. Importantly, the pharmacologic PI 3'-kinase inhibitor, LY294002, blocked TEL-JAK2 factor-independent growth and phosphorylation of protein kinase B. However, LY294002 did not alter STAT5 tyrosine phosphorylation, indicating that STAT5 and protein kinase B activation mediated by TEL-JAK2 are independent signaling pathways. Therefore, activation of the PI 3'-kinase signaling pathway is an important event mediated by TEL-JAK2 chromosomal translocations.
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PMID:TEL-JAK2 mediates constitutive activation of the phosphatidylinositol 3'-kinase/protein kinase B signaling pathway. 1143 25

Alveolar macrophages (AM) are the first line of defense against infection in the lungs. We previously showed that the production of superoxide and hydrogen peroxide, i.e., the respiratory burst, is stimulated by adenine nucleotides (ADP >> ATP) in rat AM through signaling pathways involving calcium and protein kinase C. Here, we further show that ADP induces a rapid increase in the tyrosine phosphorylation of several proteins that was reduced by the tyrosine kinase inhibitor genistein, which also inhibited the respiratory burst. Interestingly, ADP did not trigger the activation of the mitogen-activated protein kinases ERK1 and ERK2, or that of protein kinase B/AKT, a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway. This is in contrast to another stimulus of the respiratory burst, zymosan-activated serum (ZAS), which activates both the ERK and PI3K pathways. Thus, this study demonstrates that the receptor for ADP in rat AM is not coupled to the ERK and AKT pathways and, that neither the ERK pathway nor AKT is essential to induce the activation of the NAPDH oxidase by ADP in rat AM while tyrosine kinases appeared to be required. The rate and amount of hydrogen peroxide released by the ADP-stimulated respiratory burst was similar to that produced by ZAS stimulation. The absence of ERK activation after ADP stimulation therefore suggests that hydrogen peroxide is not sufficient to activate the ERK pathway in rat AM. Nonetheless, as hydrogen peroxide was necessary for ERK activation by ZAS, this indicates that, in contrast to ADP, ZAS stimulates a pathway that is targeted by hydrogen peroxide and leads to ERK activation.
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PMID:ADP stimulates the respiratory burst without activation of ERK and AKT in rat alveolar macrophages. 1152 53

The growth factor receptor-bound protein-2 (GRB2) is essential for multiple cellular functions. Inhibition of GRB2 function impairs developmental processes in various organisms and blocks transformation and proliferation of various cell types. GRB2 is most well known for its ability to link the epidermal growth factor receptor tyrosine kinase to the activation of RAS and its downstream kinases, ERK1,2. We recently reported that GRB2 does not link the HER2 tyrosine kinase to the activation of ERK1,2 but to another kinase, AKT. So, different tyrosine kinases may converge on GRB2 for signaling; however, they may not always use GRB2 to effect the same downstream kinases for cellular functions. It is likely that GRB2 will be found to regulate many more kinases because it plays such a pivotal role in signal transduction.
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PMID:GRB2: a pivotal protein in signal transduction. 1170 5

The CDC42 regulated non-receptor tyrosine kinase ACK-2 has been associated with integrin signaling. In this report, the effect of ACK-2 on the modulation of cell spreading and motility was examined. HeLa cells expressing epitope-tagged wild type ACK-2 showed a slower rate of spreading on fibronectin when compared with untransfected cells. An ACK-2 protein lacking its SH3 domain was still capable of modulating HeLa cell spreading suggesting that its tyrosine kinase activity is sufficient to induce the observed phenotype. The ACK-2 effect on the rate of cell spreading did not involve inhibition of integrin-mediated activation of PI-3K signaling, since it did not alter membrane translocation of a GFP-PH-AKT domain (AKT pleckstrin homology domain) used as a reporter for PI-3K products induced by cell adhesion. The ACK-2 effect appears to be upstream from the adapter protein CrkII, since co-expression of CrkII and ACK-2 results in a neutralization of ACK-2 mediated effects on HeLa cell spreading. Similarly, co-expression of p130Cas, which interacts with the adapter protein CrkII, with ACK-2, also results in a partial reversion of the ACK-2 effects on cell spreading. CrkII mediated reversal of the ACK-2 induced phenotype requires the activity of the small GTPase, Rap1. Co-expression of ACK-2 and CrkII with a dominant negative form of Rap1 reverses the neutralization by CrkII suggesting that CrkII mediated activation of Rap1 is required. However, an active form of Rap1 is not sufficient to reverse the ACK-2 phenotype by itself. A role for Rac1 in ACK-2 effects was also established. An activated Rac1 protein neutralized the ACK-2 mediated inhibition of cell spreading. A direct measurement of cell motility by either a modified Boyden chamber or wounding assay demonstrates that ACK-2 overexpression increases the motility of the cells. These results suggest that ACK-2 modulates HeLa cells spreading upstream of pathways regulated by CrkII and that ACK-2 may regulate cell motility by controlling the activation of small GTPases such as Rap1 and Rac1.
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PMID:Modulation of HeLa cells spreading by the non-receptor tyrosine kinase ACK-2. 1183 91

Interleukin-6 (IL-6) is a prominent tumor growth factor for malignant multiple myeloma cells. In addition to its known activation of the Janus tyrosine kinase-STAT and RAS-MEK-ERK pathways, recent work suggests that IL-6 can also activate the phosphatidylinositol 3-kinase (PI3-K)/AKT kinase pathway in myeloma cells. Because activation of the PI3-K/AKT as well as RAS-MEK-ERK pathways may result in downstream stimulation of the p70(S6K) (p70) and phosphorylation of the 4E-BP1 translational repressor, we assessed these potential molecular targets in IL-6-treated myeloma cells. IL-6 rapidly activated p70 kinase activity and p70 phosphorylation. Activation was inhibited by wortmannin, rapamycin, and the ERK inhibitors PD98059 and UO126, as well as by a dominant negative mutant of AKT. The concurrent requirements for both ERK and PI3-K/AKT appeared to be a result of their ability to phosphorylate p70 on different residues. In contrast, IL-6-induced phosphorylation of 4E-BP1 was inhibited by rapamycin, wortmannin, and dominant negative AKT but ERK inhibitors had no effect, indicating ERK function was dispensable. In keeping with these data, a dominant active AKT mutant was sufficient to induce 4E-BP1 phosphorylation but could not by itself activate p70 kinase activity. Prevention of IL-6-induced p70 activation and 4E-BP1 phosphorylation by the mammalian target of rapamycin inhibitors rapamycin and CCI-779 resulted in inhibition of IL-6-induced myeloma cell growth. These results indicate that both ERK and PI3-K/AKT pathways are required for optimal IL-6-induced p70 activity, but PI3-K/AKT is sufficient for 4E-BP1 phosphorylation. Both effects are mediated via mammalian target of rapamycin function, and, furthermore, these effects are critical for IL-6-induced tumor cell growth.
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PMID:Signal pathways involved in activation of p70S6K and phosphorylation of 4E-BP1 following exposure of multiple myeloma tumor cells to interleukin-6. 1187 47

We have previously shown that 4-anilinoquinazolines can be potent inhibitors of vascular endothelial growth factor (VEGF) receptor (Flt-1 and KDR) tyrosine kinase activity. A novel subseries of 4-anilinoquinazolines that possess basic side chains at the C-7 position of the quinazoline nucleus have been synthesized. This subseries contains potent, nanomolar inhibitors of KDR (median IC(50) 0.02 microM, range 0.001-0.04 microM), which are comparatively less potent vs Flt-1 tyrosine kinase (median IC(50) 0.55 microM, range 0.02-1.6 microM). The compounds also retain some inhibitory activity against the tyrosine kinase associated to the endothelial growth factor receptor (EGFR) (median IC(50) 0.2 microM, range 0.075-0.8 microM) but demonstrate selectivity vs that associated to the FGF receptor 1 (median IC(50) 2.5 microM, range 0.9-19 microM). This selectivity profile is also evident in a growth factor-stimulated human endothelial cell (HUVEC) proliferation assay (i.e., inhibition of VEGF > EGF > FGF), with inhibition of VEGF-induced proliferation being achieved at nanomolar concentrations (median IC(50) 0.06 microM). Further examination of compound 2 (ZD6474) in recombinant enzyme assays revealed excellent selectivity for the inhibition of KDR tyrosine kinase (IC(50) 0.04 microM) vs the kinase activity of erbB2, MEK, CDK-2, Tie-2, IGFR-1R, PDK, PDGFRbeta, and AKT (IC(50) range: 1.1 to >100 microM). Anilinoquinazolines possessing basic C-7 side chains exhibited markedly improved aqueous solubility over previously described anilinoquinazolines possessing neutral C-7 side chains (up to 500-fold improvement at pH 7.4). In addition, aqueous solubility of the neutral fraction present at pH 7.4 of the basic subseries of anilinoquinazoline proved to be higher than that of the neutral analogue 1 (ZD4190). Oral administration of representative compounds to mice (50 mg/kg) produced plasma levels between 0.2 and 3 microM at 24 h after dosing. Our development candidate 2 demonstrated a very attractive in vitro profile combined with excellent solubility (330 microM at pH 7.4) and good oral bioavailability in rat and dog (> 80 and > 50%, respectively). This compound demonstrated highly significant, dose-dependent, antitumor activity in athymic mice. Once daily oral administration of 100 mg/kg of compound 2 for 21 days inhibited the growth of established Calu-6 lung carcinoma xenografts by 79% (P < 0.001, Mann Whitney rank sum test), and substantial inhibition (36%, P < 0.02) was evident with 12.5 mg/kg/day.
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PMID:Novel 4-anilinoquinazolines with C-7 basic side chains: design and structure activity relationship of a series of potent, orally active, VEGF receptor tyrosine kinase inhibitors. 1188 99


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