title: Beta-catenin phosphorylated at threonine 120 antagonizes generation of active beta-catenin by spatial localization in trans-Golgi network.
abstract: The stability and subcellular localization of beta-catenin, a protein that plays a major role in cell adhesion and proliferation, is tightly regulated by multiple signaling pathways. While aberrant activation of beta-catenin signaling has been implicated in cancers, the biochemical identity of transcriptionally active beta-catenin (ABC), commonly known as unphosphorylated serine 37 (S37) and threonine 41 (T41) β-catenin, remains elusive. Our current study demonstrates that ABC transcriptional activity is influenced by phosphorylation of T120 by Protein Kinase D1 (PKD1). Whereas the nuclear β-catenin from PKD1-low prostate cancer cell line C4-2 is unphosphorylated S37/T41/T120 with high transcription activity, the nuclear β-catenin from PKD1-overexpressing C4-2 cells is highly phosphorylated at T120, S37 and T41 with low transcription activity, implying that accumulation of nuclear β-catenin alone cannot be simply used as a read-out for Wnt activation. In human normal prostate tissue, the phosphorylated T120 β-catenin is mainly localized to the trans-Golgi network (TGN, 22/30, 73%), and this pattern is significantly altered in prostate cancer (14/197, 7.1%), which is consistent with known down regulation of PKD1 in prostate cancer. These in vitro and in vivo data unveil a previously unrecognized post-translational modification of ABC through T120 phosphorylation by PKD1, which alters subcellular localization and transcriptional activity of β-catenin. Our results support the view that β-catenin signaling activity is regulated by spatial compartmentation and post-translational modifications and protein level of β-catenin alone is insufficient to count signaling activity.
authors.affiliation: Department of Surgery, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America. cheng.du@umassmed.edu
authors.forename: Cheng
authors.initials: C
authors.lastname: Du
authors.forename: Chuanyou
authors.initials: C
authors.lastname: Zhang
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Li
authors.forename: Md Helal Uddin
authors.initials: MH
authors.lastname: Biswas
authors.forename: K C
authors.initials: KC
authors.lastname: Balaji
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010766:Phosphorylation; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism*; D013912:Threonine / Q000737:chemistry / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D021601:trans-Golgi Network / Q000378:metabolism*
chemical_list: D051176:beta Catenin; D013912:Threonine