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, O., Dorey, K., Simon, V., Barila', D., Superti Furga, G., Roche, S. (2002). c-Abl is an effector of Src for growth factor-induced c-myc expression and DNA synthesis. EMBO JOURNAL, 21(4), 514-524.

c-Abl is an effector of Src for growth factor-induced c-myc expression and DNA synthesis

BARILA', DANIELA;
2002-02-15

Abstract

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.
15-feb-2002
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/18 - GENETICA
English
Con Impact Factor ISI
Proto-Oncogene Proteins c-abl; Proto-Oncogene Proteins pp60(c-src); Cells, Cultured; Genes, myc; Animals; Mitosis; Signal Transduction; Mice; DNA Replication; Molecular Sequence Data; Phosphorylation; Amino Acid Sequence; Platelet-Derived Growth Factor; Cytoplasm
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC125864/?tool=pubmed
Furstoss, O., Dorey, K., Simon, V., Barila', D., Superti Furga, G., Roche, S. (2002). c-Abl is an effector of Src for growth factor-induced c-myc expression and DNA synthesis. EMBO JOURNAL, 21(4), 514-524.
Furstoss, O; Dorey, K; Simon, V; Barila', D; Superti Furga, G; Roche, S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/10560
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