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J Cell Biochem 2012, PMID: 22173835

Upregulation of mTORC2 activation by the selective agonist of EPAC, 8-CPT-2Me-cAMP, in prostate cancer cells: assembly of a multiprotein signaling complex.

Misra, Uma K; Pizzo, Salvatore V

Ligation of cell surface-associated GRP78 by activated α(2) -macroglobulin triggers pro-proliferative cellular responses. In part, this results from activation of adenylyl cyclase leading to an increase in cAMP. We have previously employed the cAMP analog 8-CPT-2Me-cAMP to probe these responses. Here we show in 1-LN prostate cancer cells that 8-CPT-2Me-cAMP causes a dose-dependent increase in Epac1, p-Akt(T308) , p-Akt(S473) , but not p-CREB. By contrast, the PKA activator 6-Benz-cAMP caused a dose-dependent increase in p-CREB, but not Epac1. We measured mTORC2-dependent Akt phosphorylation at S473 in immunoprecipitates of mTOR or Rictor from 1-LN cells. 8-CPT-2Me-cAMP caused a two-threefold increase in p-Akt(S473) and Akt(S473) kinase activity in Rictor immunoprecipitates. By contrast, there was only a negligible effect on p-Akt(T308) in Rictor immunoprecipitates. Silencing Rictor gene expression by RNAi significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of Akt at Ser(473) . These studies represent the first report that Epac1 mediates mTORC2-dependent phosphorylation of Akt(S473) . Pretreatment of these cells with the PI 3-Kinase inhibitor LY294002 significantly suppressed 8-CPT-2Me-cAMP-dependent p-Akt(S473) and p-Akt(S473) kinase activities, and both effects were rapamycin insensitive. This treatment caused a two to threefold increase in S6 Kinase and 4EBP1 phosphorylation, indices of mTORC1 activation. Pretreatment of the cells with LY294002 and rapamycin significantly suppressed 8-CPT-2Me-cAMP-induced phosphorylation of S6 Kinase and 4EBP1. We further demonstrate that in 8-CPT-2Me-cAMP-treated cells, Epac1 co-immunoprecipitates with AKAP, Raptor, Rictor, PDE3B, and PDE4D suggesting thereby that during Epac1-induced activation of mTORC1 and mTORC2, Epac1 may have an additional function as a "scaffold" protein.

Diseases/Pathways annotated by Medline MESH: Prostatic Neoplasms
Document information provided by NCBI PubMed

Text Mining Data

Akt → mTORC2: " We measured mTORC2 dependent Akt phosphorylation at S473 in immunoprecipitates of mTOR or Rictor from 1-LN cells "

p-Akt → 8-CPT-2Me-cAMP: " 8-CPT-2Me-cAMP caused a two-threefold increase in p-Akt ( S473 ) and Akt ( S473 ) kinase activity in Rictor immunoprecipitates "

Akt ⊣ Rictor: " Silencing Rictor gene expression by RNAi significantly suppressed 8-CPT-2Me-cAMP induced phosphorylation of Akt at Ser ( 473 ) "

Akt → 8-CPT-2Me-cAMP: " Silencing Rictor gene expression by RNAi significantly suppressed 8-CPT-2Me-cAMP induced phosphorylation of Akt at Ser ( 473 ) "

Akt → mTORC2: " These studies represent the first report that Epac1 mediates mTORC2 dependent phosphorylation of Akt ( S473 ) "

p-Akt → 8-CPT-2Me-cAMP: " Pretreatment of these cells with the PI 3-Kinase inhibitor LY294002 significantly suppressed 8-CPT-2Me-cAMP dependent p-Akt ( S473 ) and p-Akt ( S473 ) kinase activities, and both effects were rapamycin insensitive "

4EBP1 → 8-CPT-2Me-cAMP: " Pretreatment of the cells with LY294002 and rapamycin significantly suppressed 8-CPT-2Me-cAMP induced phosphorylation of S6 Kinase and 4EBP1 "

mTORC1 → Epac1: " We further demonstrate that in 8-CPT-2Me-cAMP treated cells, Epac1 co-immunoprecipitates with AKAP, Raptor, Rictor, PDE3B, and PDE4D suggesting thereby that during Epac1 induced activation of mTORC1 and mTORC2, Epac1 may have an additional function as a `` scaffold '' protein "

mTORC2 → Epac1: " We further demonstrate that in 8-CPT-2Me-cAMP treated cells, Epac1 co-immunoprecipitates with AKAP, Raptor, Rictor, PDE3B, and PDE4D suggesting thereby that during Epac1 induced activation of mTORC1 and mTORC2 , Epac1 may have an additional function as a `` scaffold '' protein "

Manually curated Databases

No curated data.