ArticleJournal of molecular signaling2013
Differential PKA activation and AKAP association determines cell fate in cancer cells.
Article in Journal of molecular signaling, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- Article
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- A Cre-dependent reporter mouse for quantitative real-time imaging of protein kinase A activity dynamics.Scientific reports · 2024Article
- A Cre-dependent reporter mouse for quantitative real-time imaging of Protein Kinase A activity dynamics.bioRxiv : the preprint server for biology · 2023Article
- The Emerging Role of RNA N6-Methyladenosine Modification in Pancreatic Cancer.Frontiers in oncology · 2022Review
- m6A demethylase FTO suppresses pancreatic cancer tumorigenesis by demethylatingMolecular therapy. Nucleic acids · 2021Article
- TGFβ and IGF1R signaling activates protein kinase A through differential regulation of ezrin phosphorylation in colon cancer cells.The Journal of biological chemistry · 2018Article
- Article
- Ubiquitylation of MFHAS1 by the ubiquitin ligase praja2 promotes M1 macrophage polarization by activating JNK and p38 pathways.Cell death & disease · 2017Article
- Adenoid cystic carcinoma: current therapy and potential therapeutic advances based on genomic profiling.Oncotarget · 2015Review
- AKAP3 correlates with triple negative status and disease free survival in breast cancer.BMC cancer · 2015Article
- Ezrin expression and cell survival regulation in colorectal cancer.Cellular signalling · 2014Article
- Role of calmodulin-calmodulin kinase II, cAMP/protein kinase A and ERK 1/2 on Aeromonas hydrophila-induced apoptosis of head kidney macrophages.PLoS pathogens · 2014Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
backgroundThe dependence of malignant properties of colorectal cancer (CRC) cells on IGF1R signaling has been demonstrated and several IGF1R antagonists are currently in clinical trials. Recently, we identified a novel pathway in which cAMP independent PKA activation by TGFβ signaling resulted in the destabilization of survivin/XIAP complex leading to increased cell death. In this study, we evaluated the effect of IGF1R inhibition or activation on PKA activation and its downstream cell survival signaling mechanisms.
methodsSmall molecule IGF1R kinase inhibitor OSI-906 was used to test the effect of IGF1R inhibition on PKA activation, AKAP association and its downstream cell survival signaling. In a complementary approach, ligand mediated activation of IGF1R was performed and AKAP/PKA signaling was analyzed for their downstream survival effects.
resultsWe demonstrate that the inhibition of IGF1R in the IGF1R-dependent CRC subset generates cell death through a novel mechanism involving TGFβ stimulated cAMP independent PKA activity that leads to disruption of cell survival by survivin/XIAP mediated inhibition of caspase activity. Importantly, ligand mediated activation of the IGF1R in CRC cells results in the generation of cAMP dependent PKA activity that functions in cell survival by inhibiting caspase activity. Therefore, this subset of CRC demonstrates 2 opposing pathways organized by 2 different AKAPs in the cytoplasm that both utilize activation of PKA in a manner that leads to different outcomes with respect to life and death. The cAMP independent PKA activation pathway is dependent upon mitochondrial AKAP149 for its apoptotic functions. In contrast, Praja2 (Pja2), an AKAP-like E3 ligase protein was identified as a key element in controlling cAMP dependent PKA activity and pro-survival signaling. Genetic manipulation of AKAP149 and Praja2 using siRNA KD had opposing effects on PKA activity and survivin/XIAP regulation.
conclusionsWe had identified 2 cytoplasmic pathways dependent upon the same enzymatic activity with opposite effects on cell fate in terms of life and death. Understanding the specific mechanistic functions of IGF1R with respect to determining the PKA survival functions would have potential for impact upon the development of new therapeutic strategies by exploiting the IGF1R/cAMP-PKA survival signaling in cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.