title: Subcellular localization and Ser-137 phosphorylation regulate tumor-suppressive activity of profilin-1.
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.
authors: From the Center for Alzheimer's and Neurodegenerative Diseases, University of Texas, Southwestern Medical Center, Dallas, Texas 75390.
authors: Marc I
authors: MI
authors: Diamond
authors: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230.
authors: Shirong
authors: S
authors: Cai
authors: Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143.
authors: Aaron
authors: A
authors: Boudreau
authors: Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors: Clifton J
authors: CJ
authors: Carey
authors: Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri 63130.
authors: Nicholas
authors: N
authors: Lyle
authors: Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri 63130.
authors: Rohit V
authors: RV
authors: Pappu
authors: Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors: S Joshua
authors: SJ
authors: Swamidass
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, and.
authors: Mina
authors: M
authors: Bissell
authors: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230.
authors: Helen
authors: H
authors: Piwnica-Worms
authors: Breast Oncology Program, Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110 jshao1@dom.wustl.edu.
authors: Jieya
authors: J
authors: Shao
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016147:Genes, Tumor Suppressor; D006801:Humans; D010766:Phosphorylation; D051304:Profilins / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism*
chemical_list: C495738:PFN1 protein, human; D051304:Profilins; D012694:Serine
keywords: Apoptosis; Cancer; Cell Compartmentalization; Nucleus; Phosphorylation; Profilin; Proliferation