Dual alterations in casein kinase I-epsilon and GSK-3beta modulate beta-catenin stability in hyperproliferating colonic epithelia.
Casein kinase I (CKI)-epsilon and GSK-3beta phosphorylate beta-catenin at Ser(45) (beta-cat(45)) and Thr(41)/Ser(37,33) (beta-cat(33,37,41)) residues, thereby facilitating its ubiquitination and proteasomal degradation. We used a Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model to determine Ser/Thr phosphorylation and biological function of beta-catenin during crypt hyperproliferation. TMCH was associated with 3-fold ... and 3.3-fold increases in CKI-epsilon cellular abundance and 2-fold and 1.8-fold increase in its activity at 6 and 12 days after infection, respectively. beta-Catenin coimmunoprecipitated with both cellular and nuclear CKI-epsilon and cellular axin at these time points. Cellular beta-catenin was constitutively phosphorylated at Ser(45) and underwent subcellular redistribution to cytoskeletal and nuclear fractions at days 6 and 12 of TMCH, respectively. beta-cat(33,37,41), however, exhibited only subtle changes in either phosphorylation status or subcellular distribution even after blocking proteasomal degradation in vivo. Interestingly, GSK-3beta underwent increased phosphorylation at Ser(9), leading to 40% and 70% decreases in its activity at these time points, respectively. Coimmunoprecipitation studies exhibited strong association of GSK-3beta with PKC-zeta at either time point. Cellular beta-cat(45) stabilized and, along with unphosphorylated beta-catenin, underwent nuclear translocation, associated with nuclear accumulated Tcf-4 and cAMP response element binding protein binding protein, and was significantly acetylated, leading to increases in DNA binding. Priming of beta-catenin at Ser(45) exists in vivo. However, beta-cat(45) does not necessarily enter the degradation pathway. Impairment in linking beta-cat(45) to subsequent GSK-3beta-mediated phosphorylation and degradation may account for increased steady-state levels of both unphosphorylated as well as Ser(45)-phosphorylated beta-catenin, which may be causally linked to increases in cell census during TMCH.
Mesh Terms:
Animals, Boronic Acids, Casein Kinase Iepsilon, Cell Nucleus, Citrobacter rodentium, Colon, Cyclic AMP Response Element-Binding Protein, Cytoskeleton, DNA, Enterobacteriaceae Infections, Glycogen Synthase Kinase 3, Hyperplasia, Immunoprecipitation, Intestinal Mucosa, Mice, Phosphorylation, Protease Inhibitors, Proteasome Endopeptidase Complex, Protein Binding, Protein Kinase C, Pyrazines, Repressor Proteins, Serine, TCF Transcription Factors, Threonine, beta Catenin
Animals, Boronic Acids, Casein Kinase Iepsilon, Cell Nucleus, Citrobacter rodentium, Colon, Cyclic AMP Response Element-Binding Protein, Cytoskeleton, DNA, Enterobacteriaceae Infections, Glycogen Synthase Kinase 3, Hyperplasia, Immunoprecipitation, Intestinal Mucosa, Mice, Phosphorylation, Protease Inhibitors, Proteasome Endopeptidase Complex, Protein Binding, Protein Kinase C, Pyrazines, Repressor Proteins, Serine, TCF Transcription Factors, Threonine, beta Catenin
Am. J. Physiol. Gastrointest. Liver Physiol.
Date: Feb. 01, 2007
PubMed ID: 17053159
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