Cripto-1 induces phosphatidylinositol 3'-kinase-dependent phosphorylation of AKT and glycogen synthase kinase 3beta in human cervical carcinoma cells.
Cripto-1 (CR-1), a member of the epidermal growth factor-CFC peptide family, activates the ras/raf/mitogen-activated protein/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway. In the present study, the role of CR-1 in the phosphatidylinositol 3'-kinase (PI3K)/AKT (protein kinase B)/glycogen synthase kinase 3beta (GSK-3beta)-dependent signaling pathway was evaluated in human SiHa cervical carcinoma cells. Our data demonstrate that CR-1 can enhance the tyrosine phosphorylation of the p85 regulatory subunit of PI3K and transiently induce the phosphorylation of AKT in a time- and dose-dependent manner. In addition, CR-1 was found to induce the phosphorylation of GSK-3beta. Phosphorylation of AKT and GSK-3beta by CR-1 can be blocked by LY294002, a specific inhibitor of PI3K, thus leading to apoptosis. Finally, the apoptotic effect of LY294002 can be partially rescued by exogenous CR-1. In summary, our data suggest that human CR-1 may function as a survival factor through a PI3K-dependent signaling pathway involving AKT and GSK-3beta.
Ebert
A D
AD
National Cancer Institute, Laboratory of Tumor Immunology and Biology, Tumor Growth Factor Section, National Institutes of Health, Bethesda, Maryland 20892, USA.
Wechselberger
C
C
Frank
S
S
Wallace-Jones
B
B
Seno
M
M
Martinez-Lacaci
I
I
Bianco
C
C
De Santis
M
M
Weitzel
H K
HK
Salomon
D S
DS
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor; D005260:Female; D058851:GPI-Linked Proteins; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002867:Chromones; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D058851:GPI-Linked Proteins; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009025:Morpholines; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; C070636:TDGF1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human