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

Frontiers in Cell and Developmental Biology

卷:9

Shirong Cai¹  Faliang Wang³  Jieya Shao⁴  Sun-Joong Kim⁴  Cuige Zhu⁴  Aaron Boudreau⁵  Mina Bissell⁵ 

[1] Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;

[2] Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States;

[3] Department of Surgical Oncology, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China;

[4] Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States;

[5] Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, United States;

关键词: profilin-1;    phosphorylation;    actin;    poly-L-proline;    apoptosis;    breast cancer;   

DOI  :  10.3389/fcell.2021.692269

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown