Activation of phosphoinositide 3-OH kinase by the alpha6beta4 integrin promotes carcinoma invasion.
We demonstrate that the alpha6beta4 integrin promotes carcinoma invasion through a preferential and localized targeting of phosphoinositide-3 OH kinase (PI3K) activity. Stable expression of alpha6beta4 increased carcinoma invasion in a PI3K-dependent manner, and transient expression of a constitutively active PI3K increased invasion in the absence of alpha6beta4. Ligation of alpha6beta4 stimulated significantly more PI3K activity than ligation of beta1 integrins, establishing specificity among integrins for PI3K activation. Alpha6beta4-regulated PI3K activity was required for the formation of lamellae, dynamic sites of motility, in carcinoma cells. The small G protein Rac is required downstream of PI3K for invasion. These studies define a mechanism by which the alpha6beta4 integrin promotes carcinoma invasion and invoke a novel function for PI3K signaling.
Shaw
L M
LM
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Rabinovitz
I
I
Wang
H H
HH
Toker
A
A
Mercurio
A M
AM
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000939:Epitopes / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D039161:Integrin alpha6beta4; D016023:Integrins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000077191:Wortmannin; D020744:rac GTP-Binding Proteins
D000730:Androstadienes; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D000939:Epitopes; D039161:Integrin alpha6beta4; D016023:Integrins; D019869:Phosphatidylinositol 3-Kinases; D019893:Ribosomal Protein S6 Kinases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins; D000077191:Wortmannin