Regulation of Neuronal Survival by the Serine-Threonine Protein Kinase Akt

Dudek, Henryk; Datta, Sandeep Robert; Franke, Thomas; Birnbaum, Morris J.; Yao, Ryoji; Cooper, Geoffrey M.; Segal, Rosalind A.; Kaplan, David R.; Greenberg, Michael E.

doi:10.1126/science.275.5300.661

Cited by 2,307 publications

(1,819 citation statements)

References 36 publications

Supporting

Mentioning

1,733

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, elevated K + levels do not activate PI3-kinase and elicit neuronal survival in the presence of PI3-kinase inhibitors (D'Mello et al, 1997). In these cells, PI3-kinase activation of the serine/ threonine kinase Akt/PKB is necessary for IGF-Iinduced survival but not for the anti-apoptotic e ect of K + -ions (Dudek et al, 1997).…”

Section: Discussionmentioning

confidence: 92%

“…Moreover, overexpression of constitutively active forms of the PI3-kinase target Akt/PKB has been shown to be su cient to block apoptosis in a number of cell types (Dudek et al, 1997;Kulik et al, 1997;Kau mannZeh et al, 1997;Khwaja et al, 1997). NGFstimulated TrkA activates PI3-kinase in both PC12 cells and in ®broblasts expressing TrkA (Carter and Downes, 1992;Ra oni and Bradshaw, 1992;Solto et al, 1992;Ohmichi et al, 1992).…”

Section: Resultsmentioning

confidence: 99%

“…Both, the MAPK and the PI3-kinase pathways seem to be required for IGF-I to inhibit apoptosis of di erentiated PC12 cells following NGF withdrawal (Parrizas et al, 1997). An anti-apoptotic role of PI3-kinase is further supported by the ®nding that the PI3-kinase-activated serine/threonine kinase Akt/PKB is required for IGF-Iinduced survival of serum-deprived neurones (Dudek et al, 1997) and by the observation that activated Akt/ PKB is su cient to block U.V.-induced apoptosis in ®broblasts (Kulik et al, 1997). Furthermore, activated forms of both PI3-kinase and Akt/PKB suppress c-Myc induced apoptosis in Rat-1MycER TM cells when overexpressed (Kau mann-Zeh et al, 1997).…”

Section: Introductionmentioning

confidence: 97%

See 2 more Smart Citations

Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

View full text Add to dashboard Cite

Survival signalling by ligand-activated tyrosine kinase receptors plays a crucial role in maintaining the balance between cell viability and apoptosis in multicellular organisms. To identify receptor domains and pathways involved in survival signalling, the nerve growth factor receptor TrkA was expressed in Rat-1/MycER TM ®broblasts. We demonstrate that wt-TrkA receptor delays c-Myc-, U.V.-and Cycloheximide-induced apoptosis and activates targets such as the mitogen-activated protein kinase (MAPK) Erk2 and the serine/threonine kinase Akt/PKB, both of which have been implicated in survival signalling. TrkA mutated within its SHC binding site (Y490F) delays c-Myc-induced apoptosis without activating endogenous Akt/PKB. In contrast, the TrkA Y490F mutant receptor does not delay U.V.-induced apoptosis whilst TrkA mutated at its PLC-g binding site (Y785F) is capable of protecting from apoptosis induced by c-Myc or U.V. treatment. The double mutant TrkA YY490/785FF fails to block either of these two apoptotic stimuli. While PI3-kinase inhibitors LY294002 and Wortmannin competely block survival signalling following U.V. treatment, neither drug a ects the ability of TrkA to block c-Myc-induced apoptosis. We show that the Akt/PKB pathway is essential for NGF stimulated TrkA survival signalling in the case of U.V.-induced apoptosis, but that apoptosis induced by c-Myc is also blocked by a novel, Akt/PKB-independent, pathway. These observations suggest that TrkA can activate di erent survival signalling pathways, which can interfere with speci®c apoptotic pathways.

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

View full text Add to dashboard Cite

show abstract

“…Hyperactivation of mTORC1 in certain cell types results in suppression of AKT kinase activity through negative feedback, which is reflected by the hypophosphorylation of Thr308 and Ser493 (Harrington et al , 2004; Manning, 2004; Rozengurt et al , 2014). Since AKT has a known anti‐apoptotic activity (Ahmed et al , 1997; Dudek et al , 1997; Kauffmann‐Zeh et al , 1997; Kennedy et al , 1997), a potential inhibition of AKT could be involved in the observed cell death. However, in a panel of BL cell lines, TSC1 knockdown either resulted in an increase in Ser493 phosphorylation or did not change Ser493 phosphorylation of AKT, while we were unable to detect any Thr308 phosphorylation in our assay (Fig EV4A).…”

Section: Resultsmentioning

confidence: 99%

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

et al. 2018

View full text Add to dashboard Cite

The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient‐sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC‐driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR‐15a. TSC1 knockdown results in elevated mTORC1‐dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC‐driven cancers.

show abstract

“…The first option is unlikely as DA SNpc loss is estimated to be 60%–70% at the onset of symptoms (Fearnley & Lees, 1991; Lang & Lozano, 1998). Favoring the second option is the report that, after binding to D 2 receptors, dopamine can be internalized to form a signaling complex (including ß‐arrestin and protein phosphatase 2) that regulates the Akt pathway (Beaulieu et al, 2008), a cascade involved in neuroprotection (Dudek et al, 1997; Soler et al, 1999). Dopamine inhibits GABA A ‐mediated synaptic inputs to intrinsic striatal neurons (Bracci, Centonze, Bernardi, & Calabresi, 2002; Momiyama & Koga, 2001; Pisani, Bonsi, Centonze, Calabresi, & Bernardi, 2000) through presynaptic D 2 receptors (Centonze et al, 2003; for a review, see Berke, 2011).…”

Section: Discussionmentioning

confidence: 99%

Substantia nigra dopaminergic neurons and striatal interneurons are engaged in three parallel but interdependent postnatal neurotrophic circuits

Sanchez-Garcia

Nieto-González

García-Junco-Clemente

et al. 2018

Aging Cell

View full text Add to dashboard Cite

The striatum integrates motor behavior using a well‐defined microcircuit whose individual components are independently affected in several neurological diseases. The glial cell line‐derived neurotrophic factor (GDNF), synthesized by striatal interneurons, and Sonic hedgehog (Shh), produced by the dopaminergic neurons of the substantia nigra (DA SNpc), are both involved in the nigrostriatal maintenance but the reciprocal neurotrophic relationships among these neurons are only partially understood. To define the postnatal neurotrophic connections among fast‐spiking GABAergic interneurons (FS), cholinergic interneurons (ACh), and DA SNpc, we used a genetically induced mouse model of postnatal DA SNpc neurodegeneration and separately eliminated Smoothened (Smo), the obligatory transducer of Shh signaling, in striatal interneurons. We show that FS postnatal survival relies on DA SNpc and is independent of Shh signaling. On the contrary, Shh signaling but not dopaminergic striatal innervation is required to maintain ACh in the postnatal striatum. ACh are required for DA SNpc survival in a GDNF‐independent manner. These data demonstrate the existence of three parallel but interdependent neurotrophic relationships between SN and striatal interneurons, partially defined by Shh and GDNF. The definition of these new neurotrophic interactions opens the search for new molecules involved in the striatal modulatory circuit maintenance with potential therapeutic value.

show abstract

Regulation of Neuronal Survival by the Serine-Threonine Protein Kinase Akt

Cited by 2,307 publications

References 36 publications

Specific TrkA survival signals interfere with different apoptotic pathways

Specific TrkA survival signals interfere with different apoptotic pathways

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

Substantia nigra dopaminergic neurons and striatal interneurons are engaged in three parallel but interdependent postnatal neurotrophic circuits

Contact Info

Product

Resources

About