schliessen

Filtern

 

Bibliotheken

A transforming mutation in the pleckstrin homology domain of AKT1 in cancer

Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, c... Full description

Journal Title: Nature 2007, Vol.448(7152), p.439
Main Author: John D. Carpten
Other Authors: Andrew L. Faber , Candice Horn , Gregory P. Donoho , Stephen L. Briggs , Christiane M. Robbins , Galen Hostetter , Sophie Boguslawski , Tracy Y. Moses , Stephanie Savage , Mark Uhlik , Aimin Lin , Jian Du , Yue-Wei Qian , Douglas J. Zeckner , Greg Tucker-Kellogg , Jeffrey Touchman , Ketan Patel , Spyro Mousses , Michael Bittner , Richard Schevitz , Mei-Huei T. Lai , Kerry L. Blanchard , James E. Thomas
Format: Electronic Article Electronic Article
Language:
Subjects:
ID: ISSN: 0028-0836 ; E-ISSN: 1476-4687 ; DOI: 10.1038/nature05933
Link: http://dx.doi.org/10.1038/nature05933
Zum Text:
SendSend as email Add to Book BagAdd to Book Bag
Staff View
recordid: nature_a10.1038/nature05933
title: A transforming mutation in the pleckstrin homology domain of AKT1 in cancer
format: Article
creator:
  • John D. Carpten
  • Andrew L. Faber
  • Candice Horn
  • Gregory P. Donoho
  • Stephen L. Briggs
  • Christiane M. Robbins
  • Galen Hostetter
  • Sophie Boguslawski
  • Tracy Y. Moses
  • Stephanie Savage
  • Mark Uhlik
  • Aimin Lin
  • Jian Du
  • Yue-Wei Qian
  • Douglas J. Zeckner
  • Greg Tucker-Kellogg
  • Jeffrey Touchman
  • Ketan Patel
  • Spyro Mousses
  • Michael Bittner
  • Richard Schevitz
  • Mei-Huei T. Lai
  • Kerry L. Blanchard
  • James E. Thomas
subjects:
  • Blood Proteins -- Genetic Aspects
  • Protein Kinases -- Genetic Aspects
  • Protein Kinases -- Physiological Aspects
  • Gene Mutation -- Health Aspects
  • Cancer -- Genetic Aspects
  • Cancer -- Development And Progression
  • Cellular Signal Transduction -- Health Aspects
ispartof: Nature, 2007, Vol.448(7152), p.439
description: Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.
language:
source:
identifier: ISSN: 0028-0836 ; E-ISSN: 1476-4687 ; DOI: 10.1038/nature05933
fulltext: fulltext
issn:
  • 0028-0836
  • 00280836
  • 1476-4687
  • 14764687
url: Link


@attributes
ID1831317185
RANK0.07
NO1
SEARCH_ENGINEprimo_central_multiple_fe
SEARCH_ENGINE_TYPEPrimo Central Search Engine
LOCALfalse
PrimoNMBib
record
control
sourcerecordid10.1038/nature05933
sourceidnature_a
recordidTN_nature_a10.1038/nature05933
sourcesystemPC
pqid21171862
galeid185560846
display
typearticle
titleA transforming mutation in the pleckstrin homology domain of AKT1 in cancer
creatorJohn D. Carpten ; Andrew L. Faber ; Candice Horn ; Gregory P. Donoho ; Stephen L. Briggs ; Christiane M. Robbins ; Galen Hostetter ; Sophie Boguslawski ; Tracy Y. Moses ; Stephanie Savage ; Mark Uhlik ; Aimin Lin ; Jian Du ; Yue-Wei Qian ; Douglas J. Zeckner ; Greg Tucker-Kellogg ; Jeffrey Touchman ; Ketan Patel ; Spyro Mousses ; Michael Bittner ; Richard Schevitz ; Mei-Huei T. Lai ; Kerry L. Blanchard ; James E. Thomas
ispartofNature, 2007, Vol.448(7152), p.439
identifier
source
descriptionAlthough AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.
subjectBlood Proteins -- Genetic Aspects ; Protein Kinases -- Genetic Aspects ; Protein Kinases -- Physiological Aspects ; Gene Mutation -- Health Aspects ; Cancer -- Genetic Aspects ; Cancer -- Development And Progression ; Cellular Signal Transduction -- Health Aspects;
version11
lds50peer_reviewed
links
openurl$$Topenurl_article
backlink$$Uhttp://dx.doi.org/10.1038/nature05933$$EView_this_record_in_Nature
openurlfulltext$$Topenurlfull_article
search
creatorcontrib
0John D. Carpten
1Andrew L. Faber
2Candice Horn
3Gregory P. Donoho
4Stephen L. Briggs
5Christiane M. Robbins
6Galen Hostetter
7Sophie Boguslawski
8Tracy Y. Moses
9Stephanie Savage
10Mark Uhlik
11Aimin Lin
12Jian Du
13Yue-Wei Qian
14Douglas J. Zeckner
15Greg Tucker-Kellogg
16Jeffrey Touchman
17Ketan Patel
18Spyro Mousses
19Michael Bittner
20Richard Schevitz
21Mei-Huei T. Lai
22Kerry L. Blanchard
23James E. Thomas
titleA transforming mutation in the pleckstrin homology domain of AKT1 in cancer
general
0Nature Publishing Group
110.1038/nature05933
2nature.com (Nature Publishing Group)
sourceidnature_a
recordidnature_a10.1038/nature05933
issn
00028-0836
100280836
21476-4687
314764687
rsrctypearticle
creationdate2007
searchscopenature_a
scopenature_a
lsr30VSR-Enriched:[pqid, galeid, eissn, date, description, subject, pages]
sort
titleA transforming mutation in the pleckstrin homology domain of AKT1 in cancer
authorJohn D. Carpten ; Andrew L. Faber ; Candice Horn ; Gregory P. Donoho ; Stephen L. Briggs ; Christiane M. Robbins ; Galen Hostetter ; Sophie Boguslawski ; Tracy Y. Moses ; Stephanie Savage ; Mark Uhlik ; Aimin Lin ; Jian Du ; Yue-Wei Qian ; Douglas J. Zeckner ; Greg Tucker-Kellogg ; Jeffrey Touchman ; Ketan Patel ; Spyro Mousses ; Michael Bittner ; Richard Schevitz ; Mei-Huei T. Lai ; Kerry L. Blanchard ; James E. Thomas
creationdate20070704
facets
frbrgroupid8466516846620675440
frbrtype5
creationdate2007
collectionnature.com (Nature Publishing Group)
prefilterarticles
rsrctypearticles
creatorcontrib
0John D. Carpten
1Andrew L. Faber
2Candice Horn
3Gregory P. Donoho
4Stephen L. Briggs
5Christiane M. Robbins
6Galen Hostetter
7Sophie Boguslawski
8Tracy Y. Moses
9Stephanie Savage
10Mark Uhlik
11Aimin Lin
12Jian Du
13Yue-Wei Qian
14Douglas J. Zeckner
15Greg Tucker-Kellogg
16Jeffrey Touchman
17Ketan Patel
18Spyro Mousses
19Michael Bittner
20Richard Schevitz
21Mei-Huei T. Lai
22Kerry L. Blanchard
23James E. Thomas
jtitleNature
toplevelpeer_reviewed
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
au
0John D. Carpten
1Andrew L. Faber
2Candice Horn
3Gregory P. Donoho
4Stephen L. Briggs
5Christiane M. Robbins
6Galen Hostetter
7Sophie Boguslawski
8Tracy Y. Moses
9Stephanie Savage
10Mark Uhlik
11Aimin Lin
12Jian Du
13Yue-Wei Qian
14Douglas J. Zeckner
15Greg Tucker-Kellogg
16Jeffrey Touchman
17Ketan Patel
18Spyro Mousses
19Michael Bittner
20Richard Schevitz
21Mei-Huei T. Lai
22Kerry L. Blanchard
23James E. Thomas
atitleA transforming mutation in the pleckstrin homology domain of AKT1 in cancer
jtitleNature
risdate20070704
volume448
issue7152
spage439
issn0028-0836
genrearticle
ristypeJOUR
pubNature Publishing Group
doi10.1038/nature05933
pages439-444
eissn14764687
date2007-07-26