Ser71 Phosphorylation Inhibits Actin-Binding of Profilin-1 and Its Apoptosis-Sensitizing Activity

Wang, Faliang; Zhu, Cuige; Cai, Shirong; Boudreau, Aaron; Kim, Sun-Joong; Bissell, Mina; Shao, Jieya

doi:10.3389/fcell.2021.692269

Ser⁷¹ Phosphorylation Inhibits Actin-Binding of Profilin-1 and Its Apoptosis-Sensitizing Activity

Journal Article · Mon Jun 21 00:00:00 EDT 2021 · Frontiers in Cell and Developmental Biology

DOI:https://doi.org/10.3389/fcell.2021.692269· OSTI ID:1816029

Wang, Faliang ^[1]; Zhu, Cuige ^[2]; Cai, Shirong ^[3]; Boudreau, Aaron ^[4]; Kim, Sun-Joong ^[2]; Bissell, Mina ^[4]; Shao, Jieya ^[2]

Washington Univ., St. Louis, MO (United States). Dept. of Medicine. Division of Oncology; National Clinical Research Center for Child Health, Hangzhou (China). Zhejiang Univ. School of Medicine. The Children’s Hospital. Dept. of Surgical Oncology; OSTI
Washington Univ., St. Louis, MO (United States). Dept. of Medicine. Division of Oncology
Washington Univ., St. Louis, MO (United States). School of Medicine. Dept. of Cell Biology and Physiology; Univ. of Houston, TX (United States). MD Anderson Cancer Center
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division

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.

View Accepted Manuscript (DOE)

Sponsoring Organization:: American Cancer Society; Breast Cancer Research Foundation (BCRF); National Institutes of Health (NIH); National Natural Science Foundation of China (NSFC); Susan G. Komen Foundation; USDOD; USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1816029

Journal Information:: Frontiers in Cell and Developmental Biology, Journal Name: Frontiers in Cell and Developmental Biology Vol. 9; ISSN 2296-634X

Publisher:: Frontiers Media S.A.Copyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
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Ser71 Phosphorylation Inhibits Actin-Binding of Profilin-1 and Its Apoptosis-Sensitizing Activity

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Ser⁷¹ Phosphorylation Inhibits Actin-Binding of Profilin-1 and Its Apoptosis-Sensitizing Activity