Ser71 Phosphorylation Inhibits Actin-Binding of Profilin-1 and Its Apoptosis-Sensitizing Activity
| Autor: | F. Wang, Mina J. Bissell, Jieya Shao, Shirong Cai, Cuige Zhu, Aaron Boudreau, Sun-Joong Kim |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
QH301-705.5
Cell profilin-1 chemotherapy Dephosphorylation Cell and Developmental Biology 03 medical and health sciences breast cancer 0302 clinical medicine Profilin-1 medicine Biology (General) Protein kinase A Nuclear export signal Actin Original Research 030304 developmental biology 0303 health sciences phosphorylation Chemistry apoptosis Cell Biology Cell biology medicine.anatomical_structure 030220 oncology & carcinogenesis Phosphorylation protein kinase A poly-L-proline actin Nuclear localization sequence Developmental Biology |
| Zdroj: | Frontiers in Cell and Developmental Biology, Vol 9 (2021) Frontiers in Cell and Developmental Biology |
| ISSN: | 2296-634X |
| Popis: | The essential actin-binding factor profilin-1 (Pfn1) is a non-classical tumor suppressor with the abilities toboth inhibit cellular proliferation and augment chemotherapy-induced apoptosis. Besides actin, Pfn1 interacts with proteins harboring the poly-L-proline (PLP) motifs. Our recent work demonstrated that both nuclear localization and PLP-binding are required for tumor growth inhibition by Pfn1, and this is at least partially due to Pfn1 association with the PLP-containing ENL protein in the Super Elongation Complex (SEC) and the transcriptional inhibition of pro-cancer genes. In this paper, by identifying a phosphorylation event of Pfn1 at Ser71 capable of inhibiting its actin-binding and nuclear export, we provide in vitro and in vivo evidence that chemotherapy-induced apoptotic sensitization by Pfn1 requires its cytoplasmic localization and actin-binding. With regard to tumor growth inhibition byPfn1, our data indicate a requirement for dynamic actin association and dissociation rendered by reversible Ser71phosphorylation and dephosphorylation. Furthermore, genetic and pharmacological experiments showed that Ser71 of Pfn1 can be phosphorylated by protein kinase A (PKA). Taken together, our data provide novel mechanistic insights into the multifaceted anticancer activities of Pfn1 and how they are spatially-defined in the cell and differentially regulated by ligand-binding. |
| Databáze: | OpenAIRE |
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