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- Publisher Website: 10.1016/j.ccell.2014.08.017
- Scopus: eid_2-s2.0-84907967403
- WOS: WOS:000343343800009
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Article: Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors
Title | Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors |
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Authors | |
Issue Date | 2014 |
Citation | Cancer Cell, 2014, v. 26, n. 4, p. 479-494 How to Cite? |
Abstract | © 2014 Elsevier Inc. PIK3R1 (p85α regulatory subunit of PI3K) is frequently mutated across cancer lineages. Herein, we demonstrate that the most common recurrent PIK3R1 mutation PIK3R1R348* and a nearby mutation PIK3R1L370fs, in contrast to wild-type and mutations in other regions of PIK3R1, confers an unexpected sensitivity to MEK and JNK inhibitors invitro and invivo. Consistent with the response to inhibitors, PIK3R1R348* and PIK3R1L370fs unexpectedly increase JNK and ERK phosphorylation. Surprisingly, p85α R348* and L370fs localize to the nucleus where the mutants provide a scaffold for multiple JNK pathway components facilitating nuclear JNK pathway activation. Our findings uncover an unexpected neomorphic role for PIK3R1R348* and neighboring truncation mutations in cellular signaling, providing a rationale for therapeutic targeting of these mutant tumors. |
Persistent Identifier | http://hdl.handle.net/10722/225062 |
ISSN | 2023 Impact Factor: 48.8 2023 SCImago Journal Rankings: 17.507 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Cheung, LydiaW T. | - |
dc.contributor.author | Yu, Shuangxing | - |
dc.contributor.author | Zhang, Dong | - |
dc.contributor.author | Li, Jie | - |
dc.contributor.author | Ng, PatrickK S. | - |
dc.contributor.author | Panupinthu, Nattapon | - |
dc.contributor.author | Mitra, Shreya | - |
dc.contributor.author | Ju, Zhenlin | - |
dc.contributor.author | Yu, Qinghua | - |
dc.contributor.author | Liang, Han | - |
dc.contributor.author | Hawke, DavidH | - |
dc.contributor.author | Lu, Yiling | - |
dc.contributor.author | Broaddus, RussellR | - |
dc.contributor.author | Mills, GordonB | - |
dc.date.accessioned | 2016-04-18T11:16:40Z | - |
dc.date.available | 2016-04-18T11:16:40Z | - |
dc.date.issued | 2014 | - |
dc.identifier.citation | Cancer Cell, 2014, v. 26, n. 4, p. 479-494 | - |
dc.identifier.issn | 1535-6108 | - |
dc.identifier.uri | http://hdl.handle.net/10722/225062 | - |
dc.description.abstract | © 2014 Elsevier Inc. PIK3R1 (p85α regulatory subunit of PI3K) is frequently mutated across cancer lineages. Herein, we demonstrate that the most common recurrent PIK3R1 mutation PIK3R1R348* and a nearby mutation PIK3R1L370fs, in contrast to wild-type and mutations in other regions of PIK3R1, confers an unexpected sensitivity to MEK and JNK inhibitors invitro and invivo. Consistent with the response to inhibitors, PIK3R1R348* and PIK3R1L370fs unexpectedly increase JNK and ERK phosphorylation. Surprisingly, p85α R348* and L370fs localize to the nucleus where the mutants provide a scaffold for multiple JNK pathway components facilitating nuclear JNK pathway activation. Our findings uncover an unexpected neomorphic role for PIK3R1R348* and neighboring truncation mutations in cellular signaling, providing a rationale for therapeutic targeting of these mutant tumors. | - |
dc.language | eng | - |
dc.relation.ispartof | Cancer Cell | - |
dc.title | Naturally occurring neomorphic PIK3R1 mutations activate the MAPK pathway, dictating therapeutic response to MAPK pathway inhibitors | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1016/j.ccell.2014.08.017 | - |
dc.identifier.scopus | eid_2-s2.0-84907967403 | - |
dc.identifier.volume | 26 | - |
dc.identifier.issue | 4 | - |
dc.identifier.spage | 479 | - |
dc.identifier.epage | 494 | - |
dc.identifier.eissn | 1878-3686 | - |
dc.identifier.isi | WOS:000343343800009 | - |
dc.identifier.f1000 | 719709847 | - |
dc.identifier.issnl | 1535-6108 | - |