title: Terminal regions of β-catenin are critical for regulating its adhesion and transcription functions.
abstract: β-Catenin, the central molecule of canonical Wnt signaling pathway, has multiple binding partners and performs many roles in the cell. Apart from being a transcriptional activator, β-catenin acts as a crucial effector component of cadherin/catenin complex to physically interact with actin cytoskeleton along with α-catenin and E-cadherin for regulating cell-cell adhesion. Here, we have generated a library of β-catenin point and deletion mutants to delineate regions within β-catenin that are important for α-catenin-β-catenin interaction, nuclear localization, and transcriptional activity of β-catenin. We observed a unique mechanism for nuclear localization of β-catenin and its mutants and show that N-terminal exon-3 region and C-terminal domain of β-catenin are critical for this activity of β-catenin. Furthermore, we show HepG2 cells have high β-catenin mediated transcriptional activity due to the presence of an interstitial deletion at the N-terminal region of β-catenin. Due to this deletion mutant (hereupon called TM), GSK3β and HDAC inhibitors failed to show any impact whereas curcumin significantly inhibited β-catenin mediated transcriptional activity reiterating that TM is primarily responsible for the high transcriptional activity of HepG2 cells. Moreover, we show the recombinant TM does not physically interact with α-catenin, localizes predominantly in the nucleus, and has nearly two-fold higher transcriptional activity than the wildtype β-catenin.
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), New Delhi, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, J&K, India.
authors.forename: Mohd Saleem
authors.initials: MS
authors.lastname: Dar
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), New Delhi, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, J&K, India.
authors.forename: Paramjeet
authors.initials: P
authors.lastname: Singh
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), New Delhi, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, J&K, India.
authors.forename: Gurjinder
authors.initials: G
authors.lastname: Singh
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), New Delhi, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, J&K, India.
authors.forename: Gayatri
authors.initials: G
authors.lastname: Jamwal
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), New Delhi, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, J&K, India.
authors.forename: Syed Sajad
authors.initials: SS
authors.lastname: Hussain
authors.affiliation: School of Life Sciences, Central University of Himachal Pradesh, Himachal Pradesh, India.
authors.forename: Aarti
authors.initials: A
authors.lastname: Rana
authors.affiliation: School of Life Sciences, Central University of Himachal Pradesh, Himachal Pradesh, India.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Akhter
authors.affiliation: Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, USA.
authors.forename: Satdarshan P
authors.initials: SP
authors.lastname: Monga
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), New Delhi, India; Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Jammu, J&K, India. Electronic address: jamal@iiim.res.in.
authors.forename: Mohd Jamal
authors.initials: MJ
authors.lastname: Dar
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D003474:Curcumin / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D017384:Sequence Deletion; D013329:Structure-Activity Relationship; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D051178:alpha Catenin / Q000378:metabolism; D051176:beta Catenin / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D051178:alpha Catenin; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D003474:Curcumin
keywords: Beta-catenin signaling; Cancer; Cell proliferation and differentiation; Cellular signaling; HepG2 cells; Transcription factors