%A Wang,Faliang
%A Zhu,Cuige
%A Cai,Shirong
%A Boudreau,Aaron
%A Kim,Sun-Joong
%A Bissell,Mina
%A Shao,Jieya
%D 2021
%J Frontiers in Cell and Developmental Biology
%C
%F
%G English
%K profilin-1 (Pfn1),Phosphorylation,Actin,poly-L-proline (PLP),Apoptosis,breast cancer,chemotherapy,Protein kinase A (PKA)
%Q
%R 10.3389/fcell.2021.692269
%W
%L
%M
%P
%7
%8 2021-June-21
%9 Original Research
%#
%! Ser71 phosphorylation of Pfn1
%*
%<
%T Ser71 Phosphorylation Inhibits Actin-Binding of Profilin-1 and Its Apoptosis-Sensitizing Activity
%U https://www.frontiersin.org/articles/10.3389/fcell.2021.692269
%V 9
%0 JOURNAL ARTICLE
%@ 2296-634X
%X 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.