title: A novel role for drebrin in regulating progranulin bioactivity in bladder cancer.
abstract: We recently established a critical role for the growth factor progranulin in bladder cancer insofar as progranulin promotes urothelial cancer cell motility and contributes, as an autocrine growth factor, to the transformed phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin expression is upregulated in invasive bladder cancer tissues compared to normal controls. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. In this study, we searched for novel progranulin-interacting proteins using pull-down assays with recombinant progranulin and proteomics. We discovered that drebrin, an F-actin binding protein, bound progranulin in urothelial cancer cells. We characterized drebrin function in urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates motility, invasion and anchorage-independent growth. In addition, drebrin regulates tumor formation in vivo and its expression is upregulated in bladder cancer tissues compared to normal tissue controls. Our data are translationally relevant as indicate that drebrin exerts an essential functional role in the regulation of progranulin action and may constitute a novel target for therapeutic intervention in bladder tumors. In addition, drebrin may serve as novel biomarker for bladder cancer.
authors.affiliation: Department of Urology and Biology of Prostate Cancer Program, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Shi-Qiong
authors.initials: SQ
authors.lastname: Xu
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Buraschi
authors.affiliation: Department of Urology and Biology of Prostate Cancer Program, Thomas Jefferson University, Philadelphia, PA, USA.|Department of Health and Endocrinology, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Alaide
authors.initials: A
authors.lastname: Morcavallo
authors.affiliation: Department of Urology and Biology of Prostate Cancer Program, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Genua
authors.affiliation: Department of Neurobiology and Behavior, Gunma University School of Medicine, Showamachi, Maebashi, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Shirao
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.affiliation: Department of Urology and Biology of Prostate Cancer Program, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Birbe
authors.affiliation: Department of Health and Endocrinology, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
authors.affiliation: Department of Pathology, Anatomy and Cell Biology and Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.affiliation: Department of Urology and Biology of Prostate Cancer Program, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morrione
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D000077153:Progranulins; D011485:Protein Binding; D040901:Proteomics / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019459:Urothelium / Q000378:metabolism / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000077153:Progranulins; C499308:Rag2 protein, mouse; C053386:drebrins; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: bladder cancer; drebrin; invasion and anchorage-independent growth; migration; progranulin
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