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Defective Rac-mediated proliferation and survival after targeted mutation of the beta(1) integrin cytodomain

Hirsch, E; Barberis, L; Brancaccio, M; Azzolino, O; Xu, DZ; Kyriakis, JM; Silengo, L; Giancotti, FG; Tarone, G and Fässler, Reinhard LU , et al. (2002) In Journal of Cell Biology 157(3). p.481-492
Abstract
Cell matrix adhesion is required for cell proliferation and survival. Here we report that mutation by gene targeting of the cytoplasmic tail of beta(1) integrin leads to defective proliferation and survival both in vivo and in vitro. Primary murine embryonic fibroblasts (MEFs) derived from mutant homozygotes display defective cell cycle coupled to impaired activation of the FAK-P13K-Akt and Rac-JNK signaling pathways. Expression in homozygous MEFs of a constitutively active form of Rac is able to rescue proliferation, survival, and JNK activation. Moreover, although showing normal Erk phosphorylation, mutant cells fail to display Erk nuclear translocation upon fibronectin adhesion. However, expression of the constitutively activated form... (More)
Cell matrix adhesion is required for cell proliferation and survival. Here we report that mutation by gene targeting of the cytoplasmic tail of beta(1) integrin leads to defective proliferation and survival both in vivo and in vitro. Primary murine embryonic fibroblasts (MEFs) derived from mutant homozygotes display defective cell cycle coupled to impaired activation of the FAK-P13K-Akt and Rac-JNK signaling pathways. Expression in homozygous MEFs of a constitutively active form of Rac is able to rescue proliferation, survival, and JNK activation. Moreover, although showing normal Erk phosphorylation, mutant cells fail to display Erk nuclear translocation upon fibronectin adhesion. However, expression of the constitutively activated form of Rac restores Erk nuclear localization, suggesting that adhesion-dependent Rac activation is necessary to integrate signals directed to promote MAPK activity. Altogether, our data provide the evidence for an epistatic interaction between the beta(1) integrin cytoplasmic domain and Rac, and indicate that this anchorage-dependent signaling pathway is crucial for cell growth control. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cytodomain, integrin, MAPK, RAC, proliferation
in
Journal of Cell Biology
volume
157
issue
3
pages
481 - 492
publisher
Rockefeller University Press
external identifiers
  • pmid:11980921
  • wos:000176427000012
  • scopus:0037193467
ISSN
0021-9525
DOI
10.1083/jcb.200111065
language
English
LU publication?
yes
id
30bd145d-9812-4b4f-bcaa-9c0f42c4a044 (old id 334829)
date added to LUP
2007-10-22 09:07:21
date last changed
2017-12-10 03:44:10
@article{30bd145d-9812-4b4f-bcaa-9c0f42c4a044,
  abstract     = {Cell matrix adhesion is required for cell proliferation and survival. Here we report that mutation by gene targeting of the cytoplasmic tail of beta(1) integrin leads to defective proliferation and survival both in vivo and in vitro. Primary murine embryonic fibroblasts (MEFs) derived from mutant homozygotes display defective cell cycle coupled to impaired activation of the FAK-P13K-Akt and Rac-JNK signaling pathways. Expression in homozygous MEFs of a constitutively active form of Rac is able to rescue proliferation, survival, and JNK activation. Moreover, although showing normal Erk phosphorylation, mutant cells fail to display Erk nuclear translocation upon fibronectin adhesion. However, expression of the constitutively activated form of Rac restores Erk nuclear localization, suggesting that adhesion-dependent Rac activation is necessary to integrate signals directed to promote MAPK activity. Altogether, our data provide the evidence for an epistatic interaction between the beta(1) integrin cytoplasmic domain and Rac, and indicate that this anchorage-dependent signaling pathway is crucial for cell growth control.},
  author       = {Hirsch, E and Barberis, L and Brancaccio, M and Azzolino, O and Xu, DZ and Kyriakis, JM and Silengo, L and Giancotti, FG and Tarone, G and Fässler, Reinhard and Altruda, F},
  issn         = {0021-9525},
  keyword      = {cytodomain,integrin,MAPK,RAC,proliferation},
  language     = {eng},
  number       = {3},
  pages        = {481--492},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Cell Biology},
  title        = {Defective Rac-mediated proliferation and survival after targeted mutation of the beta(1) integrin cytodomain},
  url          = {http://dx.doi.org/10.1083/jcb.200111065},
  volume       = {157},
  year         = {2002},
}