Integration of TGF-beta and Ras/MAPK signaling through p53 phosphorylation.
During development and tissue homeostasis, cells must integrate different signals. We investigated how cell behavior is controlled by the combined activity of transforming growth factor-beta (TGF-beta) and receptor tyrosine kinase (RTK) signaling, whose integration mechanism is unknown. We find that RTK/Ras/MAPK (mitogen-activated protein kinase) activity induces p53 N-terminal phosphorylation, enabling the interaction of p53 with the TGF-beta-activated Smads. This mechanism confines mesoderm specification in Xenopus embryos and promotes TGF-beta cytostasis in human cells. These data indicate a mechanism to allow extracellular cues to specify the TGF-beta gene-expression program.
Cordenonsi
Michelangelo
M
Department of Medical Biotechnologies, Section of Histology and Embryology, University of Padua, Padua, Italy.
Montagner
Marco
M
Adorno
Maddalena
M
Zacchigna
Luca
L
Martello
Graziano
G
Mamidi
Anant
A
Soligo
Sandra
S
Dupont
Sirio
S
Piccolo
Stefano
S
D019943:Amino Acid Substitution; D000818:Animals; D048149:Casein Kinase 1 epsilon / Q000378:metabolism; D048148:Casein Kinase Idelta / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004625:Embryo, Nonmammalian / Q000378:metabolism*; D047108:Embryonic Development; D004627:Embryonic Induction; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008648:Mesoderm / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014981:Xenopus; D018631:ras Proteins / Q000378:metabolism*
D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D005346:Fibroblast Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D048149:Casein Kinase 1 epsilon; D048148:Casein Kinase Idelta; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins