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)

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome in which affected individuals develop nervous system abnormalities that might reflect astrocyte dysfunction. The TSC2 gene product, tuberin, encodes a GTPase-activating protein (GAP) domain, which regulates the activity of Rap1 in vitro. To determine whether dysregulated Rap1, resulting from TSC2 inactivation, leads to increased astrocyte proliferation in vivo, we generated transgenic mice expressing activated Rap1(G12V) specifically in astrocytes. We observed no statistically significant difference in the number of astrocytes between wild-type and GFAP-Rap1(G12V) littermates in vivo; however, during log-phase growth, we observed a 25% increase in GFAP-Rap1(G12V) astrocyte doubling times compared to wild-type controls. This decreased proliferation was associated with delayed MAP kinase, but not AKT, activation. Lastly, to determine whether constitutive Rap1 activation could reverse the increased astrocyte proliferation observed in transgenic mice expressing oncogenic Ras(G12V), we generated transgenic mice expressing both Ras(G12V) and Rap1(G12V) in astrocytes. These double transgenic mice showed a striking reversion of the Ras(G12V) astrocyte growth phenotype. Collectively, these results argue that the tumor suppressor properties of tuberin are unlikely to be related to Rap1 inactivation and that Rap1 inhibits mitogenic Ras pathway signaling in astrocytes.
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PMID:Role of the Rap1 GTPase in astrocyte growth regulation. 1267 29

We sought to elucidate the role of AKT in follicle-stimulating hormone (FSH)-mediated granulosa cell (GC) differentiation. Our results define a signaling pathway in GCs whereby the inactivating phosphorylation of tuberin downstream of phosphatidylinositol (PI) 3-kinase/AKT activity leads to Rheb (Ras homolog enriched in brain) and subsequent mTOR (mammalian target of rapamycin) activation. mTOR then stimulates translation by phosphorylating p70 S6 kinase and, consequently, the 40 S ribosomal protein S6. Activation of this pathway is required for FSH-mediated induction of several follicular differentiation markers, including luteinizing-hormone receptor (LHR), inhibin-alpha, microtubule-associated protein 2D, and the PKA type IIbeta regulatory subunit. FSH also promotes activation of the transcription factor hypoxia-inducible factor-1 (HIF-1). FSH-stimulated HIF-1 activity is inhibited by the PI 3-kinase inhibitor LY294002, the Rheb inhibitor FTI-277 (farnesyltransferase inhibitor-277), and the mTOR inhibitor rapamycin. Finally, we find that the FSH-mediated up-regulation of reporter activities for LHR, inhibin-alpha, and vascular endothelial growth factor is dependent upon HIF-1 activity, because a dominant negative form of HIF-1alpha interferes with the up-regulation of these genes. These results show that FSH enhances HIF-1 activity downstream of the PI 3-kinase/AKT/Rheb/mTOR pathway in GCs and that HIF-1 activity is necessary for FSH to induce multiple follicular differentiation markers.
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PMID:Follicle-stimulating hormone activation of hypoxia-inducible factor-1 by the phosphatidylinositol 3-kinase/AKT/Ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) pathway is necessary for induction of select protein markers of follicular differentiation. 1498 27

The study of hereditary tumor syndromes has laid a solid foundation toward understanding the genetic basis of cancer. One of the latest examples comes from the study of tuberous sclerosis complex (TSC). As a member of the phakomatoses, TSC is characterized by the appearance of benign tumors, most notably in the central nervous system, kidney, heart, lung, and skin. While classically described as "hamartomas," the pathology of the lesions has features suggestive of abnormal cellular proliferation, size, differentiation, and migration. Occasionally, tumors progress to become malignant (i.e., renal cell carcinoma). The genetic basis of this disease has been attributed to mutations in one of two unlinked genes, TSC1 and TSC2. Cells undergo bi-allelic inactivation of either gene to give rise to tumors in a classic tumor suppressor "two-hit" paradigm. The functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, have remained ill defined until recently. Genetic, biochemical, and biologic analyses have highlighted their role as negative regulators of the mTOR signaling pathway. Tuberin, serving as a substrate of AKT and AMPK, mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival. Emerging evidence also suggests that the TSC 1/2 complex may play a role in modulating the activity of beta-catenin and TGFbeta. These findings provide novel functional links between the TSC genes and other tumor suppressors responsible for Cowden's disease (PTEN), Peutz-Jeghers syndrome (LKB1), and familial polyposis (APC). Common sporadic cancers such as prostate, lung, colon, endometrium, and breast have ties to these genes, highlighting the potential role of the TSC proteins in human cancers. Rapamycin, a specific mTOR inhibitor, has potent antitumoral activities in preclinical models of TSC and is currently undergoing phase I/II clinical studies.
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PMID:The tuberous sclerosis complex genes in tumor development. 1556 17

Loss-of-function mutations in the NF1 tumor suppressor gene underlie the familial cancer syndrome neurofibromatosis type I (NF1). The NF1-encoded protein, neurofibromin, functions as a Ras-GTPase activating protein (RasGAP). Accordingly, deregulation of Ras is thought to contribute to NF1 development. However, the critical effector pathways involved in disease pathogenesis are still unknown. We show here that the mTOR pathway is tightly regulated by neurofibromin. mTOR is constitutively activated in both NF1-deficient primary cells and human tumors in the absence of growth factors. This aberrant activation depends on Ras and PI3 kinase, and is mediated by the phosphorylation and inactivation of the TSC2-encoded protein tuberin by AKT. Importantly, tumor cell lines derived from NF1 patients, and a genetically engineered cell system that requires Nf1-deficiency for transformation, are highly sensitive to the mTOR inhibitor rapamycin. Furthermore, while we show that the activation of endogenous Ras leads to constitutive mTOR signaling in this disease state, we also demonstrate that in normal cells Ras is differentially required for mTOR signaling in response to various growth factors. Thus, these findings identify the NF1 tumor suppressor as an indispensable regulator of TSC2 and mTOR. Furthermore, our results also demonstrate that Ras plays a critical role in the activation of mTOR in both normal and tumorigenic settings. Finally, these data suggest that rapamycin, or its derivatives, may represent a viable therapy for NF1.
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PMID:The NF1 tumor suppressor critically regulates TSC2 and mTOR. 1593 8

The most exciting advances in the tuberous sclerosis complex (TSC) field occurred in 1993 and 1997 with the cloning of the TSC2 and TSC1 genes, respectively, and in 2003 with the identification of Rheb as the target of tuberin's (TSC2) GTPase activating protein (GAP) domain. Rheb has a dual role: it activates mTOR and inactivates B-Raf. Activation of mTOR leads to increased protein synthesis through phosphorylation of p70S6K and 4E-BP1. Upon insulin or growth factor stimulation, tuberin is phosphorylated by several kinases, including AKT/PKB, thereby suppressing its GAP activity and activating mTOR. Phosphorylation of hamartin (TSC1) by CDK1 also negatively regulates the activity of the hamartin/tuberin complex. Despite these biochemical advances, exactly how mutations in TSC1 or TSC2 lead to the clinical manifestations of TSC is far from being understood. Two of the most unusual phenotypes in TSC are the apparent metastasis of benign cells carrying TSC1 and TSC2 mutations, resulting in pulmonary lymphangiomyomatosis, and the ability of cells with TSC1 or TSC2 mutations to differentiate into the separate components of renal angiomyolipomas (vessels, smooth muscle and fat). We will discuss how the TSC signaling pathways are affected by mutations in TSC1 or TSC2, focusing on how these mutations may lead to the renal and pulmonary manifestations of TSC.
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PMID:Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease. 1628 94

Protein kinase B appears to play a key role in insulin signaling and in the control of apoptosis, although the precise targets of PKB are incompletely understood. PKB exists as three isoforms (alpha, beta, and gamma) that may have unique as well as common functions within the cell. To facilitate understanding the precise roles of PKB and its isoforms, novel tools of widespread applicability are described. These tools are antisense oligonucleotide probes that enable the specific and potent knock down of endogenous PKB alpha, beta, or gamma isoforms, individually or in various combinations, including concurrent removal of all three isoforms. The probes were applied to dissect the role of PKB in phosphorylating glycogen synthase kinase-3 (GSK-3), a critical mediator in multiple responses, and other potentially key targets. Triple antisense knock down of PKB alpha, beta, and gamma so that total PKB was <6% blocked insulin-stimulated phosphorylation of endogenous GSK-3alpha and GSK-3beta isoforms by 67% and 45%, respectively, showing that GSK-3alpha and GSK-3beta are controlled by endogenous PKB. Each PKB isoform contributed to GSK-3alpha and GSK-3beta phosphorylation, with PKBbeta having the predominant role. Knock down of total PKB incompletely blocked insulin-stimulated phosphorylation of GSK-3alpha and GSK-3beta, and a pathway involving atypical PKCs, zeta/lambda, was shown to contribute to the signal. Triple antisense knock down of PKB alpha, beta, and gamma abrogated the insulin-stimulated phosphorylation of WNK1, ATP citrate lyase, and tuberin. However, antisense-mediated knock down of PKB alpha, beta, and gamma had no effect on insulin-stimulated DNA synthesis in 3T3-L1 adipocytes, indicating that pathways other than PKB mediate this response in these cells. Finally, our PKB antisense strategy provides a method of general usefulness for further dissecting the precise targets and roles of PKB and its isoforms.
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PMID:A new strategy for studying protein kinase B and its three isoforms. Role of protein kinase B in phosphorylating glycogen synthase kinase-3, tuberin, WNK1, and ATP citrate lyase. 1638 97

Loss of tuberin, the product of TSC2 gene, increases mammalian target of rapamycin (mTOR) signaling, promoting cell growth and tumor development. However, in cells expressing tuberin, it is not known how repression of mTOR signaling is relieved to activate this pathway in response to growth factors and how hamartin participates in this process. We show that hamartin colocalizes with hypophosphorylated tuberin at the membrane, where tuberin exerts its GTPase-activating protein (GAP) activity to repress Rheb signaling. In response to growth signals, tuberin is phosphorylated by AKT and translocates to the cytosol, relieving Rheb repression. Phosphorylation of tuberin at serines 939 and 981 does not alter its intrinsic GAP activity toward Rheb but partitions tuberin to the cytosol, where it is bound by 14-3-3 proteins. Thus, tuberin bound by 14-3-3 in response to AKT phosphorylation is sequestered away from its membrane-bound activation partner (hamartin) and its target GTPase (Rheb) to relieve the growth inhibitory effects of this tumor suppressor.
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PMID:Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. 1663 47

TSC1, encoding hamartin, and TSC2, encoding tuberin, are tumor suppressor genes responsible for the autosomal dominantly inherited disease tuberous sclerosis (TSC). TSC affects approximately 1 in 6000 individuals and is characterized by the development of tumors, named hamartomas, in different organs. Hamartin and tuberin form a complex, of which tuberin is assumed to be the functional component. The TSC proteins have been implicated in the control of cell cycle and cell size. In addition to enhanced growth, reduced death rates can lead to tumor development. Therefore, defects in the apoptosis-inducing pathways contribute to neoplastic cell expansion. Here, we show that tuberin triggers apoptosis, accompanied by downregulation of p70S6K activity and of phosphorylation of BAD on residue Ser136, and by upregulation of the interaction of BAD/BCL-2 and BAD/BCL-XL. AKT phosphorylation negatively regulates tuberin's potential to trigger apoptosis. Experiments with BAD-/- cells demonstrate BAD to be a mediator of tuberin's effects on the regulation of apoptosis. Tuberin interferes with insulin-like growth factor-1-induced BAD Ser136 phosphorylation and cell survival. Our work proposes a model in which tuberin-mediated inhibition of p70S6K activates BAD to heterodimerize with BCL-2 and BCL-XL to promote apoptosis. A mutation of TSC2--as it occurs in TSC patients--attenuates this proapoptotic potential, underscoring the relevance of our findings for human pathophysiology.
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PMID:Tuberin activates the proapoptotic molecule BAD. 1670 51

Mutational activation of Ras promotes oncogenesis by controlling cell cycle regulation and cell survival. Ras-mediated activation of both, the PI3K/AKT pathway and the MEK/ERK pathway, can trigger downregulation of the function of tuberin to block the activities of mTOR and p70S6K. Here we demonstrate that Ras-induced cell survival is accompanied by upregulation of p70S6K activity. Ras harbors the potential to negatively affect tuberin-induced apoptosis and p70S6K inactivation. These effects of Ras were found to depend on its potential to regulate the MEK/ERK pathway. Experiments using tuberin-negative fibroblasts revealed that the potential of Ras to counteract apoptosis depends on functional tuberin. Taken together, we provide evidence that the function of Ras to trigger inactivation of tuberin plays a major role in the regulation of cell survival upon mutational activation of the oncogene Ras. This is the first description of a functional interaction between the tumor suppressor tuberin and the oncogene Ras in regulating apoptosis.
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PMID:Ras mediates cell survival by regulating tuberin. 1792 28

Expression of the chemokine receptor CXCR4, a G protein-coupled receptor, and HER2, a receptor tyrosine kinase, strongly correlates with the aggressive and metastatic potential of breast cancer cells. We studied estrogen regulation of CXCR4 in estrogen receptor (ER)-positive MCF-7 breast cancer cells overexpressing HER2 (MCF7-HER2). Although estrogen evoked no change in CXCR4 mRNA levels, CXCR4 protein was significantly up-regulated after estrogen treatment of these cells, whereas estrogen had no effect on CXCR4 protein level in parental MCF7 cells that are low in HER2. Use of the CXCR4 specific inhibitor, AMD 3100, indicated that this increase in CXCR4 protein was partially responsible for the increase in estrogen-induced migration of these cells. The estrogen-induced increase in CXCR4 protein in MCF-7-HER2 cells was abrogated by the antiestrogen ICI 182780 and by gefitinib (Iressa; a phospho-tyrosine kinase inhibitor), indicating an ER-mediated effect and confirming involvement of receptor tyrosine kinases, respectively. Using specific pathway inhibitors, we show that the estrogen-induced increase in CXCR4 involves PI3K/AKT, MAPK and mTOR pathways. PI3K/AKT and MAPK pathways are known to result in the phosphorylation and functional inactivation of tuberin (TSC2) of tuberous sclerosis complex thereby negating its inhibitory effects on mTOR, which in turn stimulates the translational machinery. Small interfering RNA (siRNA) mediated knockdown of tuberin elevated the level of CXCR4 protein in MCF7-HER2 cells and also nullified further estrogen up-regulation of CXCR4. This study suggests a pivotal role of PI3 K, MAPK and mTOR pathways, via tuberin, in post-transcriptional control of CXCR4, initiated through estrogen-stimulated crosstalk between ER and HER2. Thus, post-transcriptional regulation of CXCR4 by estrogens acting through ER via kinase pathways may play a critical role in determining the metastatic potential of breast cancer cells.
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PMID:Post-transcriptional regulation of chemokine receptor CXCR4 by estrogen in HER2 overexpressing, estrogen receptor-positive breast cancer cells. 1880 77


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