Characterization and tissue-specific expression of human GSK-3-binding proteins FRAT1 and FRAT2.
We have isolated the entire coding sequence of human FRAT2 (frequently rearranged in advanced T-cell lymphomas-2). It exhibits appreciable amino acid identity to FRAT1 (77%) which was initially isolated as frequently being overexpressed in a murine leukemia virus insertion model in murine tumors. FRAT proteins are thought to play a role in Wnt signaling. They can bind to glycogen synthase kinase-3 (GSK-3) and Dishevelled, two proteins involved in Wnt signal transduction. Both hFRAT1 and hFRAT2 are intronless genes localized to the same portion of chromosome 10q24.1 and separated by only 10.7 kb. In a broad range of human tissues FRAT1 and FRAT2 are readily detected and expressed in a near identical pattern. Both species are repressed when the human embryonal carcinoma cell line, NT2/D1, is induced to differentiate with all-trans retinoic acid (RA). This treatment had no appreciable effect on FRAT levels in two other RA-sensitive cell lines that were not of germ cell tumor origin. The overlapping expression patterns suggest these two genes share a regulatory region. Both FRAT genes exhibited three species of mRNA, which varied in representation between tissues. When transiently overexpressed in COS-1 cells, the FRAT proteins were detected in the cytosol and concentrated in the nucleus. Both hFRAT1 and hFRAT2 are implicated in the selective modulation of GSK-3 activity via the Wnt signaling pathway. This study provides a foundation from which to examine the role these proteins play in Wnt-dependent and -independent processes.
Freemantle
Sarah J
SJ
Department of Pharmacology and Toxicology, Dartmouth Medical School HB7650, 03755, Hanover, NH, USA
Portland
Holly B
HB
Ewings
Katherine
K
Dmitrovsky
Florence
F
DiPetrillo
Keith
K
Spinella
Michael J
MJ
Dmitrovsky
Ethan
E
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics*; D002461:Cell Line, Transformed; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D015870:Gene Expression; D049452:Green Fluorescent Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014162:Transfection; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018076:DNA, Complementary; C491819:FRAT1 protein, human; C491817:FRAT2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins