Subcellular localization and Ser-137 phosphorylation regulate tumor-suppressive activity of Profilin-1

Marc I. Diamond, Shirong Cai, Aaron Boudreau, Clifton J. Carey, Nicholas Lyle, Rohit V. Pappu, S. Joshua Swamidass, Mina Bissell, Helen Piwnica-Worms, Jieya Shao

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

The actin-binding protein profilin-1 (Pfn1) inhibits tumor growth and yet is also required for cell proliferation and survival, an apparent paradox. We previously identified Ser-137 of Pfn1 as a phosphorylation site within the poly-L-proline (PLP) binding pocket. Here we confirm that Ser-137 phosphorylation disrupts Pfn1 binding to its PLP-containing ligands with little effect on actin binding. We find in mouse xenografts of breast cancer cells that mimicking Ser-137 phosphorylation abolishes cell cycle arrest and apoptotic sensitization by Pfn1 and confers a growth advantage to tumors. This indicates a previously unrecognized role of PLP binding in Pfn1 antitumor effects. Spatial restriction of Pfn1 to the nucleus or cytoplasm indicates that inhibition of tumor cell growth by Pfn1 requires its nuclear localization, and this activity is abolished by a phosphomimetic mutation on Ser-137. In contrast, cytoplasmic Pfn1 lacks inhibitory effects on tumor cell growth but rescues morphological and proliferative defects of PFN1 null mouse chondrocytes. These results help reconcile seemingly opposed cellular effects of Pfn1, provide new insights into the antitumor mechanism of Pfn1, and implicate Ser-137 phosphorylation as a potential therapeutic target for breast cancer.

Original languageEnglish (US)
Pages (from-to)9075-9086
Number of pages12
JournalJournal of Biological Chemistry
Volume290
Issue number14
DOIs
StatePublished - Apr 3 2015

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Diamond, M. I., Cai, S., Boudreau, A., Carey, C. J., Lyle, N., Pappu, R. V., Swamidass, S. J., Bissell, M., Piwnica-Worms, H., & Shao, J. (2015). Subcellular localization and Ser-137 phosphorylation regulate tumor-suppressive activity of Profilin-1. Journal of Biological Chemistry, 290(14), 9075-9086. https://doi.org/10.1074/jbc.M114.619874