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alphavbeta5/beta6 integrin suppression leads to a stimulation of alpha2beta1 dependent cell migration resistant to PI3K/Akt inhibition.
- Source :
-
Experimental cell research [Exp Cell Res] 2009 Jul 01; Vol. 315 (11), pp. 1840-9. Date of Electronic Publication: 2009 Mar 26. - Publication Year :
- 2009
-
Abstract
- Crosstalk between integrins is involved in the regulation of various cell functions including cell migration. Here we identify the interplay between the integrins alphavbeta5/beta6 and alpha2beta1 during cell migration toward type I collagen. Human colon cancer cell lines HT29-D4 and SW480 were used as cell models. To improve our understanding of the consequences of alphavbeta5/beta6 function on alpha2beta1, we decreased the expression of alphav integrins by either siRNA or lysosomal targeting strategies or inhibited their function using, as antagonists, blocking antibodies or disintegrins. In all cases, we observed a greatly enhanced alpha2beta1 integrin-dependent cell migration associated with focal adhesion rearrangements and increased outside-in signaling as demonstrated by elevated phosphorylation of focal adhesion kinase and MAPKinase (ERK1 and ERK2). The alphavbeta5/beta6-dependent limitation of alpha2beta1 function could be overridden by TS2/16, an activating anti-beta1 antibody. Interestingly, compared to control cells, the pharmacological inhibition of PI3Kinase or the siRNA-mediated knockdown of AKT had little effect on the high alpha2beta1-mediated cell migration observed in the absence of alphav integrins or following activation of alpha2beta1 integrins by the TS2/16. These results suggest that integrins alphavbeta5/beta6 repress alpha2beta1 possibly by interfering with their activation process and thereby modify the cell signaling regulation of alpha2beta1-mediated migration.
- Subjects :
- Antigens, Neoplasm genetics
Antigens, Neoplasm physiology
Cell Line, Tumor
Cell Movement drug effects
Collagen Type I metabolism
Focal Adhesions
Humans
Integrin alpha2beta1 antagonists & inhibitors
Integrin alpha2beta1 genetics
Integrins genetics
Integrins physiology
Oncogene Protein v-akt genetics
Oncogene Protein v-akt physiology
Phosphatidylinositol 3-Kinases physiology
Protein Kinase Inhibitors pharmacology
RNA, Small Interfering genetics
Receptors, Vitronectin genetics
Receptors, Vitronectin physiology
Signal Transduction
Cell Movement physiology
Integrin alpha2beta1 physiology
Integrins antagonists & inhibitors
Oncogene Protein v-akt antagonists & inhibitors
Phosphoinositide-3 Kinase Inhibitors
Receptors, Vitronectin antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2422
- Volume :
- 315
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Experimental cell research
- Publication Type :
- Academic Journal
- Accession number :
- 19328197
- Full Text :
- https://doi.org/10.1016/j.yexcr.2009.03.014