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Article: Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer

TitleDeregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer
Authors
KeywordsAkt signaling
animal experiment
animal model
animal tissue
antineoplastic activity
Issue Date2019
PublisherNature Research (part of Springer Nature): Fully open access journals. The Journal's web site is located at http://www.nature.com/ncomms/index.html
Citation
Nature Communications, 2019, v. 10, p. article no. 716 How to Cite?
AbstractCopy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.
Persistent Identifierhttp://hdl.handle.net/10722/271375
ISSN
2017 Impact Factor: 12.353
2015 SCImago Journal Rankings: 6.539
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorLI, X-
dc.contributor.authorMak, VCY-
dc.contributor.authorZhou, Y-
dc.contributor.authorWang, C-
dc.contributor.authorWong, ESY-
dc.contributor.authorSharma, R-
dc.contributor.authorLu, Y-
dc.contributor.authorCheung, ANY-
dc.contributor.authorMills, GB-
dc.contributor.authorCheung, LWT-
dc.date.accessioned2019-06-24T01:08:39Z-
dc.date.available2019-06-24T01:08:39Z-
dc.date.issued2019-
dc.identifier.citationNature Communications, 2019, v. 10, p. article no. 716-
dc.identifier.issn2041-1723-
dc.identifier.urihttp://hdl.handle.net/10722/271375-
dc.description.abstractCopy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.-
dc.languageeng-
dc.publisherNature Research (part of Springer Nature): Fully open access journals. The Journal's web site is located at http://www.nature.com/ncomms/index.html-
dc.relation.ispartofNature Communications-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAkt signaling-
dc.subjectanimal experiment-
dc.subjectanimal model-
dc.subjectanimal tissue-
dc.subjectantineoplastic activity-
dc.titleDeregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer-
dc.typeArticle-
dc.identifier.emailMak, VCY: vicmak8@hku.hk-
dc.identifier.emailZhou, Y: yzhou@hku.hk-
dc.identifier.emailWong, ESY: esywong@hkucc.hku.hk-
dc.identifier.emailSharma, R: rasharma@hku.hk-
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hk-
dc.identifier.emailCheung, LWT: lydiacwt@hku.hk-
dc.identifier.authorityCheung, ANY=rp00542-
dc.identifier.authorityCheung, LWT=rp02137-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1038/s41467-019-08574-7-
dc.identifier.pmid30755611-
dc.identifier.pmcidPMC6372715-
dc.identifier.scopuseid_2-s2.0-85061500872-
dc.identifier.hkuros298104-
dc.identifier.volume10-
dc.identifier.spagearticle no. 716-
dc.identifier.epagearticle no. 716-
dc.publisher.placeUnited Kingdom-

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