Htid-1, the human homolog of the Drosophila melanogaster l(2)tid tumor suppressor, defines a novel physiological role of APC.
Htid-1, the human counterpart of the Drosophila tumor suppressor gene lethal(2)tumorous imaginal discs (l(2)tid) encodes three splice forms translated into three cytosolic - Tid50, Tid48 and Tid46 - and three mitochondrial - Tid43, Tid40 and Tid38 - proteins. Here we provide evidence for the association of the endogenous Tid50/Tid48 proteins with the adenomatous polyposis coli (APC) tumor suppressor in normal colon epithelium, colorectal cancer cells and mouse NIH3T3 fibroblasts. Using the Glutathione S-transferase binding assay we show that the N-terminal region including the Armadillo domain (ARM) of APC is sufficient to bind the Tid molecules. Using immunoprecipitation and confocal microscopy we show that the two molecular partners complex at defined areas of the cells with further proteins such as Hsp70, Hsc70, Actin, Dvl and Axin. Our data implicate that the formation of the complex is not associated with APC's involvement in beta-Catenin degradation. Furthermore, though it is linked to Actin it is neither associated with regulation of Actin cytoskeleton due to APC's binding to Asef nor to Tid's binding to Ras-GAP. We suggest that the novel complex acts in maintaining APC's availability for its distinct roles in the Wnt signaling important for the cell to take the right decision, either to switch the cascade OFF or ON, thus, to regulate the onset of proliferation of the cells.
Kurzik-Dumke
Ursula
U
Institute of Medical Microbiology and Hygiene, Laboratory for Comparative Tumor Biology, Johannes Gutenberg University, Obere Zahlbacher Strasse 63, 55131 Mainz, Germany. kurzik@uni-mainz.de
Czaja
Joachim
J
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes / Q000378:metabolism; D041681:NIH 3T3 Cells; D000072079:Patched Receptors; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
C576602:ARHGEF4 protein, human; D025601:Adenomatous Polyposis Coli Protein; C093721:CG5504 protein, Drosophila; C120664:DNAJA3 protein, human; D029721:Drosophila Proteins; D020662:Guanine Nucleotide Exchange Factors; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008024:Ligands; D024101:Mitochondrial Proteins; D046912:Multiprotein Complexes; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D064067:Rho Guanine Nucleotide Exchange Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D020703:ras GTPase-Activating Proteins