Enhancement of TGF-β-induced Smad3 activity by c-Abl-mediated tyrosine phosphorylation of its coactivator SKI-interacting protein (SKIP)
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675 (Japan)
- Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414 (Japan)
- Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085 (Japan)
c-Abl is a non-receptor-type tyrosine kinase that plays an important role in cell proliferation, migration, apoptosis, and fibrosis. Furthermore, although c-Abl is involved in transforming growth factor-β (TGF-β) signaling, its molecular functions in TGF-β signaling are not fully understood. Here, we found that c-Abl phosphorylates SKI-interacting protein (SKIP), a nuclear cofactor of the transcription factor Smad3. The c-Abl inhibitor imatinib suppressed TGF-β-induced expression of Smad3 targets as well as SKIP/Smad3 interaction. TGF-β-stimulation induced tyrosine phosphorylation of SKIP, and this phosphorylation was suppressed by imatinib. Tyr{sup 292}, Tyr{sup 430}, and Tyr{sup 433} residues in SKIP were shown to be involved in c-Abl-mediated phosphorylation. Phosphomimetic glutamic acid substitution at Tyr{sup 292} in SKIP enhanced, whereas its phospho-dead phenylalanine substitution attenuated TGF-β-induced SKIP/Smad3 interaction. Moreover, the phosphomimetic mutant of SKIP augmented transcriptional activity of Smad3. Taken together, these results suggest that c-Abl phosphorylates SKIP mainly at Tyr{sup 292} and promotes SKIP/Smad3 interaction for the full activation of TGF-β/Smad3 signaling. - Highlights: • c-Abl promotes TGF-β-induced SKIP/Smad3 interaction. • c-Abl phosphorylates SKIP upon TGF-β stimulation. • Phosphorylation of SKIP at Tyr{sup 292} enhances SKIP/Smad3 binding and Smad3 activity.
- OSTI ID:
- 22719057
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 490, Issue 3; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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