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c-Abl is an effector of Src for growth factor-induced c-myc expression and DNA synthesis
Olivia Furstoss1, Karel Dorey, Valérie Simon
1CNRS UPR-1086 CRBM, 1919 route de Mende, F-34293 Montpellier, France.
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.
Insights
Cytoplasmic tyrosine kinase c-Abl is crucial for platelet-derived growth factor (PDGF) and serum-induced DNA synthesis, acting as an effector of c-Src. This study reveals a novel tyrosine kinase signaling cascade (PDGFR/c-Src/c-Abl) essential for mitogenesis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The role of Src family kinases in regulating cell proliferation (mitogenesis) is not fully understood.
- Investigating the downstream effectors of Src family kinases is crucial for understanding cell growth regulation.
Purpose of the Study:
- To elucidate the mechanism by which Src family kinases regulate mitogenesis.
- To identify the role of cytoplasmic tyrosine kinase c-Abl as an effector of c-Src in DNA synthesis.
Main Methods:
- Utilized kinase-inactive mutants of c-Abl (Abl-PP-K(-)) and c-Src (SrcK295M) to inhibit their respective activities.
- Employed microinjection of neutralizing antibodies against c-Abl.
- Investigated the phosphorylation status of specific residues (Y245 and Y412) on c-Abl.
- Assessed the impact of c-Abl inhibition on p53 inactivation and c-myc expression.
Main Results:
- Inactivation of cytoplasmic c-Abl inhibited PDGF- and serum-induced DNA synthesis.
- Constitutively active c-Abl could overcome G(1) arrest induced by kinase-inactive c-Src.
- c-Src-induced c-Abl activation requires phosphorylation of Y245 and Y412.
- c-Abl function is essential for mitogen-induced c-myc expression and is dependent on active p53.
Conclusions:
- Cytoplasmic c-Abl is a key effector of c-Src in mitogenic signaling pathways.
- A signaling cascade involving PDGFR/c-Src/c-Abl is proposed to be critical for growth factor-induced DNA synthesis.
- c-Abl plays a significant role in regulating cell cycle events like p53 inactivation and c-myc expression during mitogenesis.