PI3-kinase p110α mediates β1 integrin-induced Akt activation and membrane protrusion during cell attachment and initial spreading
Zeller, Kathrin S. LU
; Idevall-Hagren, Olof
; Stefansson, Anne
; Velling, Teet
; Jackson, Shaun P.
; Downward, Julian
; Tengholm, Anders
and Johansson, Staffan
(2010)
In Cellular Signalling
22(12).
p.1838-1848
- Abstract
Integrin-mediated cell adhesion activates several signaling effectors, including phosphatidylinositol 3-kinase (PI3K), a central mediator of cell motility and survival. To elucidate the molecular mechanisms of this important pathway the specific members of the PI3K family activated by different integrins have to be identified. Here, we studied the role of PI3K catalytic isoforms in β1 integrin-induced lamellipodium protrusion and activation of Akt in fibroblasts. Real-time total internal reflection fluorescence imaging of the membrane-substrate interface demonstrated that β1 integrin-mediated attachment induced rapid membrane spreading reaching essentially maximal contact area within 5-10. min. This process required actin polymerization... (More)
Integrin-mediated cell adhesion activates several signaling effectors, including phosphatidylinositol 3-kinase (PI3K), a central mediator of cell motility and survival. To elucidate the molecular mechanisms of this important pathway the specific members of the PI3K family activated by different integrins have to be identified. Here, we studied the role of PI3K catalytic isoforms in β1 integrin-induced lamellipodium protrusion and activation of Akt in fibroblasts. Real-time total internal reflection fluorescence imaging of the membrane-substrate interface demonstrated that β1 integrin-mediated attachment induced rapid membrane spreading reaching essentially maximal contact area within 5-10. min. This process required actin polymerization and involved activation of PI3K. Isoform-selective pharmacological inhibition identified p110α as the PI3K catalytic isoform mediating both β1 integrin-induced cell spreading and Akt phosphorylation. A K756L mutation in the membrane-proximal part of the β1 integrin subunit, known to cause impaired Akt phosphorylation after integrin stimulation, induced slower cell spreading. The initial β1 integrin-regulated cell spreading as well as Akt phosphorylation were sensitive to the tyrosine kinase inhibitor PP2, but were not dependent on Src family kinases, FAK or EGF/PDGF receptor transactivation. Notably, cells expressing a Ras binding-deficient p110α mutant were severely defective in integrin-induced Akt phosphorylation, but exhibited identical membrane spreading kinetics as wild-type p110α cells.We conclude that p110α mediates β1 integrin-regulated activation of Akt and actin polymerization important for survival and lamellipodia dynamics. This could contribute to the tumorigenic properties of cells expressing constitutively active p110α.
(Less)
- author
- Zeller, Kathrin S.
LU
; Idevall-Hagren, Olof
; Stefansson, Anne
; Velling, Teet
; Jackson, Shaun P.
; Downward, Julian
; Tengholm, Anders
and Johansson, Staffan
- publishing date
- 2010-12
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- β1 integrin, Akt, Cell spreading, P110α, PI3K
- in
- Cellular Signalling
- volume
- 22
- issue
- 12
- pages
- 11 pages
- publisher
- Elsevier
- external identifiers
-
- pmid:20667469
- scopus:78650902018
- ISSN
- 0898-6568
- DOI
- 10.1016/j.cellsig.2010.07.011
- language
- English
- LU publication?
- no
- id
- 63bc5712-a2ae-458a-a508-64adf94f6ddd
- date added to LUP
- 2023-02-01 15:33:04
- date last changed
- 2024-04-03 08:23:21
@article{63bc5712-a2ae-458a-a508-64adf94f6ddd,
abstract = {{<p>Integrin-mediated cell adhesion activates several signaling effectors, including phosphatidylinositol 3-kinase (PI3K), a central mediator of cell motility and survival. To elucidate the molecular mechanisms of this important pathway the specific members of the PI3K family activated by different integrins have to be identified. Here, we studied the role of PI3K catalytic isoforms in β1 integrin-induced lamellipodium protrusion and activation of Akt in fibroblasts. Real-time total internal reflection fluorescence imaging of the membrane-substrate interface demonstrated that β1 integrin-mediated attachment induced rapid membrane spreading reaching essentially maximal contact area within 5-10. min. This process required actin polymerization and involved activation of PI3K. Isoform-selective pharmacological inhibition identified p110α as the PI3K catalytic isoform mediating both β1 integrin-induced cell spreading and Akt phosphorylation. A K756L mutation in the membrane-proximal part of the β1 integrin subunit, known to cause impaired Akt phosphorylation after integrin stimulation, induced slower cell spreading. The initial β1 integrin-regulated cell spreading as well as Akt phosphorylation were sensitive to the tyrosine kinase inhibitor PP2, but were not dependent on Src family kinases, FAK or EGF/PDGF receptor transactivation. Notably, cells expressing a Ras binding-deficient p110α mutant were severely defective in integrin-induced Akt phosphorylation, but exhibited identical membrane spreading kinetics as wild-type p110α cells.We conclude that p110α mediates β1 integrin-regulated activation of Akt and actin polymerization important for survival and lamellipodia dynamics. This could contribute to the tumorigenic properties of cells expressing constitutively active p110α.</p>}},
author = {{Zeller, Kathrin S. and Idevall-Hagren, Olof and Stefansson, Anne and Velling, Teet and Jackson, Shaun P. and Downward, Julian and Tengholm, Anders and Johansson, Staffan}},
issn = {{0898-6568}},
keywords = {{β1 integrin; Akt; Cell spreading; P110α; PI3K}},
language = {{eng}},
number = {{12}},
pages = {{1838--1848}},
publisher = {{Elsevier}},
series = {{Cellular Signalling}},
title = {{PI3-kinase p110α mediates β1 integrin-induced Akt activation and membrane protrusion during cell attachment and initial spreading}},
url = {{http://dx.doi.org/10.1016/j.cellsig.2010.07.011}},
doi = {{10.1016/j.cellsig.2010.07.011}},
volume = {{22}},
year = {{2010}},
}