Defective Rac-mediated proliferation and survival after targeted mutation of the beta1 integrin cytodomain.
Cell matrix adhesion is required for cell proliferation and survival. Here we report that mutation by gene targeting of the cytoplasmic tail of beta1 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-PI3K-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 beta1 integrin cytoplasmic domain and Rac, and indicate that this anchorage-dependent signaling pathway is crucial for cell growth control.
Hirsch
Emilio
E
Dipartimento di Genetica, Biologia, e Biochimica, Università di Torino, 10126 Torino, Italy. emilio.hirsch@unito.it
Barberis
Laura
L
Brancaccio
Mara
M
Azzolino
Ornella
O
Xu
Dazhong
D
Kyriakis
John M
JM
Silengo
Lorenzo
L
Giancotti
Filippo G
FG
Tarone
Guido
G
Fässler
Reinhard
R
Altruda
Fiorella
F
D000483:Alleles; D000818:Animals; D002448:Cell Adhesion; D002453:Cell Cycle; D002455:Cell Division; D002470:Cell Survival; D005313:Fetal Death; D005347:Fibroblasts; D018390:Gene Targeting; D006720:Homozygote; D019012:Integrin beta1 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D020744:rac GTP-Binding Proteins / Q000502:physiology*
D019012:Integrin beta1; D020033:Protein Isoforms; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D020744:rac GTP-Binding Proteins