c-Abl is an effector of Src for growth factor-induced c-myc expression and DNA synthesis.
The mechanism by which the ubiquitously expressed Src family kinases regulate mitogenesis is not well understood. Here we report that cytoplasmic tyrosine kinase c-Abl is an important effector of c-Src for PDGF- and serum-induced DNA synthesis. Inactivation of cytoplasmic c-Abl by the kinase-inactive Abl-PP-K(-) (AblP242E/P249E/K290M) or by microinjection of Abl neutralizing antibodies inhibited mitogenesis. The kinase-inactive SrcK295M induced a G(1) block that was overcome by the constitutively active Abl-PP (AblP242E/P249E). Conversely, the inhibitory effect of Abl-PP-K(-) was not compensated by Src. c-Src-induced c-Abl activation involves phosphorylation of Y245 and Y412, two residues required for c-Abl mitogenic function. Finally, we found that p53 inactivation and c-myc expression, two cell cycle events regulated by Src during mitogenesis, also implied c-Abl: c-Abl function was dispensable in cells deficient in active p53 and inhibition of c-Abl reduced mitogen-induced c-myc expression. These data identify a novel function of cytoplasmic c-Abl in the signalling pathways regulating growth factor-induced c-myc expression and we propose the existence of a tyrosine kinase signalling cascade (PDGFR/c-Src/c-Abl) important for mitogenesis.
Furstoss
Olivia
O
CNRS UPR-1086 CRBM, 1919 route de Mende, F-34293 Montpellier, France.
Dorey
Karel
K
Simon
Valérie
V
Barilà
Daniela
D
Superti-Furga
Giulio
G
Roche
Serge
S
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004261:DNA Replication / Q000502:physiology*; D016259:Genes, myc; D051379:Mice; D008938:Mitosis; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000502:physiology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000502:physiology*; D015398:Signal Transduction
D010982:Platelet-Derived Growth Factor; D016315:Proto-Oncogene Proteins c-abl; D016392:Proto-Oncogene Proteins pp60(c-src)