p53 inhibits alpha 6 beta 4 integrin survival signaling by promoting the caspase 3-dependent cleavage of AKT/PKB.
Although the interaction of matrix proteins with integrins is known to initiate signaling pathways that are essential for cell survival, a role for tumor suppressors in the regulation of these pathways has not been established. We demonstrate here that p53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase AKT/PKB. Specifically, we show that the alpha6beta4 integrin promotes the survival of p53-deficient carcinoma cells by activating AKT/PKB. In contrast, this integrin does not activate AKT/PKB in carcinoma cells that express wild-type p53 and it actually stimulates their apoptosis, in agreement with our previous findings (Bachelder, R.E., A. Marchetti, R. Falcioni, S. Soddu, and A.M. Mercurio. 1999. J. Biol. Chem. 274:20733-20737). Interestingly, we observed reduced levels of AKT/PKB protein after antibody clustering of alpha6beta4 in carcinoma cells that express wild-type p53. In contrast, alpha6beta4 clustering did not reduce the level of AKT/PKB in carcinoma cells that lack functional p53. The involvement of caspase 3 in AKT/PKB regulation was indicated by the ability of Z-DEVD-FMK, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in AKT/PKB levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of AKT/PKB in vitro. In addition, the ability of alpha6beta4 to activate AKT/PKB could be restored in p53 wild-type carcinoma cells by inhibiting caspase 3 activity. These studies demonstrate that the p53 tumor suppressor can inhibit integrin-associated survival signaling pathways.
Bachelder
R E
RE
Division of Cancer Biology and Angiogenesis, Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Ribick
M J
MJ
Marchetti
A
A
Falcioni
R
R
Soddu
S
S
Davis
K R
KR
Mercurio
A M
AM
D000951:Antigens, Neoplasm / Q000378:metabolism; D000954:Antigens, Surface / Q000502:physiology*; D014408:Biomarkers, Tumor; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D002470:Cell Survival / Q000502:physiology; D015179:Colorectal Neoplasms; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000939:Epitopes / Q000378:metabolism; D006801:Humans; D039161:Integrin alpha6beta4; D016023:Integrins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D000939:Epitopes; D039161:Integrin alpha6beta4; D016023:Integrins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases