title: NRP2 transcriptionally regulates its downstream effector WDFY1.
abstract: Neuropilins (NRPs) are cell surface glycoproteins that often act as co-receptors for plexins and VEGF family receptors. Neuropilin-2 (NRP2), a family member of NRPs, was shown to regulate autophagy and endocytic trafficking in cancer cells, a function distinctly different from its role as a co-receptor. WD Repeat and FYVE domain containing 1 (WDFY1)-protein acts downstream of NRP2 for this function. Our results indicated that NRP2 maintains an optimum concentration of WDFY1 by negatively regulating its expression. Since increased expression of WDFY1 reduces the endocytic activity, maintenance of WDFY1 level is crucial in metastatic cancer cells to sustain high endocytic activity, essential for promotion of oncogenic activation and cancer cell survival. Here, we have delineated the underlying molecular mechanism of WDFY1 synthesis by NRP2. Our results indicated that NRP2 inhibits WDFY1 transcription by preventing the nuclear localization of a transcription factor, Fetal ALZ50-reactive clone 1 (FAC1). Our finding is novel as transcriptional regulation of a gene by NRP2 axis has not been reported previously. Regulation of WDFY1 transcription by NRP2 axis is a critical event in maintaining metastatic phenotype in cancer cells. Thus, inhibiting NRP2 or hyper-activating WDFY1 can be an effective strategy to induce cell death in metastatic cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.
authors.forename: Samikshan
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.
authors.forename: Sohini
authors.initials: S
authors.lastname: Roy
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.
authors.forename: Navatha S
authors.initials: NS
authors.lastname: Polavaram
authors.affiliation: Institute of Pathology, University Hospital Carl Gustav Carus, University of Technology of Dresden, Germany.
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Baretton
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.|Institute of Pathology, University Hospital Carl Gustav Carus, University of Technology of Dresden, Germany.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Muders
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.|Fred &Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer, Omaha, Nebraska, U.S.A.
authors.forename: Surinder
authors.initials: S
authors.lastname: Batra
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.|Fred &Pamela Buffett Cancer Center, Eppley Institute for Research in Cancer, Omaha, Nebraska, U.S.A.
authors.forename: Kaustubh
authors.initials: K
authors.lastname: Datta
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D034961:Antigens, Nuclear / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D006801:Humans; D009419:Nerve Tissue Proteins / Q000502:physiology*; D039943:Neuropilin-2 / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D034961:Antigens, Nuclear; D009419:Nerve Tissue Proteins; D039943:Neuropilin-2; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C000603634:WDFY1 protein, human; C406238:fetal Alzheimer antigen; D000092468:Bromodomain Containing Proteins; C581308:neuropilin-2, human