APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-TrCP ubiquitin ligase.
Ubiquitin-dependent proteolysis is an important mechanism that suppresses the beta-catenin transcription factor in cells without Wnt stimulation. A critical step in this regulatory pathway is to create a SCF(beta-TrCP) E3 ubiquitin ligase binding site for beta-catenin. Here we show that the SCF(beta-TrCP) binding site created by phosphorylation of beta-catenin is highly vulnerable to protein phosphatase 2A (PP2A) and must be protected by the adenomatous polyposis coli (APC) tumor suppressor protein. Specifically, phosphorylated beta-catenin associated with the wild-type APC protein is recruited to the SCF(beta-TrCP) complex, ubiquitin conjugated, and degraded. A mutation in APC that deprives this protective function exposes the N-terminal phosphorylated serine/threonine residues of beta-catenin to PP2A. Dephosphorylation at these residues by PP2A eliminates the SCF(beta-TrCP) recognition site and blocks beta-catenin ubiquitin conjugation. Thus, by acting to protect the E3 ligase binding site, APC ensures the ubiquitin conjugation of phosphorylated beta-catenin.
Su
YunYun
Y
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Fu
Chunjiang
C
Ishikawa
Shinji
S
Stella
Alessandra
A
Kojima
Masayuki
M
Shitoh
Kazuhisa
K
Schreiber
Emanuel M
EM
Day
Billy W
BW
Liu
Bo
B
D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000172:deficiency / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D013379:Substrate Specificity; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D014981:Xenopus; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism*
D025601:Adenomatous Polyposis Coli Protein; C471644:BTRC protein, human; C495270:CTNNB1 protein, human; D010750:Phosphoproteins; D025801:Ubiquitin; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D044843:SKP Cullin F-Box Protein Ligases; D054648:Protein Phosphatase 2