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Regulation of Class IA PI 3-kinases

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dc.contributor.author El-Sibai, Mirvat
dc.contributor.author Wu, Haiyan
dc.contributor.author Shekar, S. Chandra
dc.contributor.author Flinn, Rory J.
dc.contributor.author Jaiswal, Bijay S.
dc.contributor.author Sen, K Ilker
dc.contributor.author Janakiraman, Vasantharajan
dc.contributor.author Seshagiri, Somasekar
dc.contributor.author Gerfen, Gary J.
dc.contributor.author Girvin, Mark E.
dc.contributor.author Backer, Jonathan M.
dc.date.accessioned 2015-11-04T13:10:39Z
dc.date.available 2015-11-04T13:10:39Z
dc.date.copyright 2009-10-07
dc.date.issued 2015-11-04
dc.identifier.issn 0027-8424 en_US
dc.identifier.uri http://hdl.handle.net/10725/2437
dc.description.abstract We previously proposed a model of Class IA PI3K regulation in which p85 inhibition of p110α requires (i) an inhibitory contact between the p85 nSH2 domain and the p110α helical domain, and (ii) a contact between the p85 nSH2 and iSH2 domains that orients the nSH2 so as to inhibit p110α. We proposed that oncogenic truncations of p85 fail to inhibit p110 due to a loss of the iSH2-nSH2 contact. However, we now find that within the context of a minimal regulatory fragment of p85 (the nSH2-iSH2 fragment, termed p85ni), the nSH2 domain rotates much more freely (τc ≈12.7 ns) than it could if it were interacting rigidly with the iSH2 domain. These data are not compatible with our previous model. We therefore tested an alternative model in which oncogenic p85 truncations destabilize an interface between the p110α C2 domain (residue N345) and the p85 iSH2 domain (residues D560 and N564). p85ni-D560K/N564K shows reduced inhibition of p110α, similar to the truncated p85ni-572STOP. Conversely, wild-type p85ni poorly inhibits p110αN345K. Strikingly, the p110αN345K mutant is inhibited to the same extent by the wild-type or truncated p85ni, suggesting that mutation of p110α-N345 is not additive with the p85ni-572STOP mutation. Similarly, the D560K/N564K mutation is not additive with the p85ni-572STOP mutant for downstream signaling or cellular transformation. Thus, our data suggests that mutations at the C2-iSH2 domain contact and truncations of the iSH2 domain, which are found in human tumors, both act by disrupting the C2-iSH2 domain interface. en_US
dc.language.iso en en_US
dc.title Regulation of Class IA PI 3-kinases en_US
dc.type Article en_US
dc.description.version Published en_US
dc.title.subtitle C2 domain-iSH2 domain contacts inhibit p85/p110α and are disrupted in oncogenic p85 mutants en_US
dc.author.school SAS en_US
dc.author.idnumber 200703859 en_US
dc.author.woa N/A en_US
dc.author.department Natural Sciences en_US
dc.description.embargo N/A en_US
dc.relation.journal National Academy of Sciences. Proceedings en_US
dc.journal.volume 106 en_US
dc.journal.issue 48 en_US
dc.article.pages 20258–20263 en_US
dc.keywords Cancer en_US
dc.keywords Glioblastoma en_US
dc.keywords Phosphoinositide 3-kinase en_US
dc.keywords PIK3CA en_US
dc.identifier.doi http://dx.doi.org/10.1073/pnas.0902369106 en_US
dc.identifier.ctation Wu, H., Shekar, S. C., Flinn, R. J., El-Sibai, M., Jaiswal, B. S., Sen, K. I., ... & Backer, J. M. (2009). Regulation of Class IA PI 3-kinases: C2 domain-iSH2 domain contacts inhibit p85/p110α and are disrupted in oncogenic p85 mutants. Proceedings of the National Academy of Sciences, 106(48), 20258-20263. en_US
dc.author.email mirvat.elsibai@lau.edu.lb
dc.identifier.url http://www.pnas.org/content/106/48/20258.short


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