Integrins and EGFR coordinately regulate the pro-apoptotic protein Bim to prevent anoikis.
Epithelial cells must adhere to the extracellular matrix (ECM) for survival, as detachment from matrix triggers apoptosis or anoikis. Integrins are major mediators of adhesion between cells and ECM proteins, and transduce signals required for cell survival. Recent evidence suggests that integrin receptors are coupled to growth factor receptors in the regulation of multiple biological functions; however, mechanisms involved in coordinate regulation of cell survival are poorly understood and mediators responsible for anoikis have not been well characterized. Here, we identify the pro-apoptotic protein Bim as a critical mediator of anoikis in epithelial cells. Bim is strongly induced after cell detachment and downregulation of Bim expression by RNA interference (RNAi) inhibits anoikis. Detachment-induced expression of Bim requires a lack of beta(1)-integrin engagement, downregulation of EGF receptor (EGFR) expression and inhibition of Erk signalling. Overexpressed EGFR was uncoupled from integrin regulation, resulting in the maintenance of Erk activation in suspension, and a block in Bim expression and anoikis. Thus, Bim functions as a key sensor of integrin and growth factor signals to the Erk pathway, and loss of such coordinate regulation may contribute to tumour progression.
Reginato
Mauricio J
MJ
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Mills
Kenna R
KR
Paulus
Jessica K
JK
Lynch
Danielle K
DK
Sgroi
Dennis C
DC
Debnath
Jayanta
J
Muthuswamy
Senthil K
SK
Brugge
Joan S
JS
D000818:Animals; D023102:Anoikis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002458:Cell Fractionation; D004791:Enzyme Inhibitors / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D016023:Integrins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D066246:ErbB Receptors