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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the TSC1 and TSC2 tumor suppressor genes give rise to the neoplastic disorders tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis. Their gene products form a complex that is a critical negative regulator of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and cell growth. We recently found that the TSC1-TSC2 complex promotes the activity of mTOR complex 2 (mTORC2), an upstream activator of Akt, and this occurs independent of its inhibitory effects on mTORC1. Loss of mTORC2 activity in cells lacking the TSC1-TSC2 complex, coupled with mTORC1-mediated feedback mechanisms, leads to strong attenuation of the growth factor-stimulated phosphorylation of Akt on S473. In this study, we show that both phosphatidylinositol 3-kinase-dependent and phosphatidylinositol 3-kinase-independent mTORC2 substrates are affected by loss of the TSC1-TSC2 complex in cell culture models and kidney tumors from both Tsc2(+/-) mice (adenoma) and TSC patients (angiomyolipoma). These mTORC2 targets are all members of the AGC kinase family and include Akt, protein kinase Calpha, and serum and glucocorticoid-induced protein kinase 1. We also show that the TSC1-TSC2 complex can directly stimulate the in vitro kinase activity of mTORC2. The interaction between these two complexes is mediated primarily through regions on TSC2 and a core component of mTORC2 called Rictor. Hence, loss of the TSC tumor suppressors results in elevated mTORC1 signaling and attenuated mTORC2 signaling. These findings suggest that the TSC1-TSC2 complex plays opposing roles in tumor progression, both blocking and promoting specific oncogenic pathways through its effects on mTORC1 inhibition and mTORC2 activation, respectively.
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PMID:Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. 1960 87

Rheb is a small GTPase primarily known for activating mammalian target of rapamycin complex 1 (mTORC1) and promoting cell growth in response to insulin and nutrients (amino acids, glucose). Shortage of glucose activates adenosine 5'-monophosphate-activated protein kinase (AMPK), which induces catabolic processes that produce ATP and suppresses energy-consuming anabolic reactions. As part of the latter response, AMPK activates the TSC1-TSC2 tumor suppressor complex, which in turn inhibits Rheb, thereby reducing mTORC1 activity and consequently suppressing protein synthesis. We recently identified an mTORC1-independent Rheb-to-AMPK feedback signaling loop in Tsc2-null in vitro models of Tuberous Sclerosis Complex (TSC). In addition to activating AMPK, Rheb reduced the nuclear levels of the cyclin-dependent kinase inhibitor p27(KIP1) (p27). Importantly, Rheb-mediated repression of p27 correlated with activation of Cdk2 and cell proliferation, and with tumor formation by TSC cells. Considering that AMPK was previously reported to regulate stability and subcellular localization of p27, we hypothesize that Rheb regulates p27 in TSC cells by activating AMPK. This article discusses how Rheb-to-AMPK, and p27 signaling may impact on disease progression and treatment of TSC, including sporadic lymphangioleiomyomatosis (S-LAM) and malignancies.
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PMID:Consequences of interrupted Rheb-to-AMPK feedback signaling in tuberous sclerosis complex and cancer. 2214 93

Lymphangioleiomyomatosis (LAM), a multisystem disease predominantly affecting premenopausal women, is associated with cystic lung destruction and lymphatic and kidney tumors. LAM results from the proliferation of a neoplastic cell that has mutations in the tuberous sclerosis complex 1 or 2 genes, leading to activation of a critical regulatory protein, mammalian target of rapamycin. In this report, we discuss the molecular mechanisms regulating LAM cell growth and report the results of therapeutic trials employing new targeted agents. At present, inhibitors of mammalian target of rapamycin such as sirolimus appear to be the most promising therapeutic agents, although drug toxicity and development of resistance are potential problems. As the pathogenesis of LAM is being further recognized, other therapeutic agents such as matrix metalloproteinase inhibitors, statins, interferon, VEGF inhibitors, chloroquine analogs and cyclin-dependent kinase inhibitors, along with sirolimus or a combination of several of these agents, may offer the best hope for effective therapy.
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PMID:Optimizing treatments for lymphangioleiomyomatosis. 2278 41

Rapamycin (sirolimus) is a fungal fermentation product that inhibits the proper functioning of a serine/threonine protein kinase in mammalian cells eponymously named mammalian target of rapamycin, or mTOR. Rapamycin is a novel class of anticancer and immunosuppressant drugs targeting the proteins at molecular level. Rapamycin (sirolimus) is routinely incorporated in drug-eluting stents used for cardiac angioplasty. In recent years, rapamycin was found to be efficacious in managing the symptom complex of tuberous sclerosis, i.e. renal angiomyolipoma, giant cell astrocytoma and pulmonary lymphangiomyomatosis. Various investigators have also proved that topically applied rapamycin causes regression of facial angiofibromas, giving better cosmetic results.
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PMID:Topical rapamycin (sirolimus) for facial angiofibromas. 2343 91

Lymphangioleiomyomatosis (LAM) is a rare multisystem disease, occurs in women, usually premenopausal, caused by the proliferation of neoplastic smooth muscle-derived cells. Mutations in the tuberous sclerosis complex genes, lead to the activation of mammalian target of rapamycin kinase (mTOR), results in proliferation of LAM cells, its increasing motility, and survival. Polycystic lung destruction, extensive involvement of lymphatic channels, chylothorax, chyloperitoneum, and renal angiomyolipomas can develop in LAM patients. The new, promising treatment strategies have been recently introduced due to discovery of the genetic and molecular mechanisms of LAM. Comprehension of the disease pathogenesis has resulted in the implementation of other therapeutic agents such as mTOR inhibitors, VEGF-D inhibitors, statins, interferon, chloroquine analogs, cyclin-dependent kinase inhibitors, matrix metalloproteinase inhibitors, aromatase inhibitors, and their combinations. The mTOR inhibitors appear to be the most important, and the efficacy of sirolimus in LAM treatment has been proved. The article discussed the new control studies with mTOR inhibitors, doxycycline, simvastatin, and combination of them in LAM patients.
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PMID:Lymphangioleiomyomatosis: New Treatment Perspectives. 2598 May 93

Lymphangioleiomyomatosis (LAM), a rare disease of women, is associated with cystic lung destruction resulting from the proliferation of abnormal smooth muscle-like LAM cells with mutations in the tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2 The mutant genes and encoded proteins are responsible for activation of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin), a drug used to treat LAM. Patients who have LAM may also be treated with bronchodilators for asthma-like symptoms due to LAM. We observed stabilization of forced expiratory volume in 1 s over time in patients receiving sirolimus and long-acting beta-agonists with short-acting rescue inhalers compared with patients receiving only sirolimus. Because beta-agonists increase cAMP and PKA activity, we investigated effects of PKA activation on the mTOR pathway. Human skin TSC2^+/- fibroblasts or LAM lung cells incubated short-term with isoproterenol (beta-agonist) showed a sirolimus-independent increase in phosphorylation of S6, a downstream effector of the mTOR pathway, and increased cell growth. Cells incubated long-term with isoproterenol, which may lead to beta-adrenergic receptor desensitization, did not show increased S6 phosphorylation. Inhibition of PKA blocked the isoproterenol effect on S6 phosphorylation. Thus, activation of PKA by beta-agonists increased phospho-S6 independent of mTOR, an effect abrogated by beta-agonist-driven receptor desensitization. In agreement, retrospective clinical data from patients with LAM suggested that a combination of bronchodilators in conjunction with sirolimus may be preferable to sirolimus alone for stabilization of pulmonary function.
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PMID:Effect of beta-agonists on LAM progression and treatment. 2933 22

Between 1993 and 2003, through experiments involving Drosophila sp., cancer biologists identified the protein kinase known as the mammalian target of rapamycin, its pathway, and its relationship to the genes responsible for tuberous sclerosis. Thereafter, clinical research has resulted in regulatory approval of mTOR inhibitors for four distinct manifestations of the disease: giant cell astrocytoma, angiomyolipoma, lymphangioleiomyomatosis, and epilepsy. These developments are summarized and the practical use of mTOR inhibitors to improve the lives of patients with tuberous sclerosis reviewed.
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PMID:mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex. 3030 23

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