A noncanonical sequence phosphorylated by casein kinase 1 in beta-catenin may play a role in casein kinase 1 targeting of important signaling proteins.
Protein kinase casein kinase 1 (CK1) phosphorylates Ser-45 of beta-catenin, "priming" the subsequent phosphorylation by glycogen synthase-3 of residues 41, 37, and 33. This concerted phosphorylation of beta-catenin signals its degradation and prevents its function in triggering cell division. The sequence around Ser-45 does not conform to the canonical consensus for CK1 substrates, which prescribes either phosphoamino acids or acidic residues in position n-3 from the target serine. However, the beta-catenin sequence downstream from Ser-45 is very similar to a sequence recognized by CK1 in nuclear factor for activated T cells 4. The common features include an SLS motif followed two to five residues downstream by a cluster of acidic residues. Synthetic peptides reproducing residues 38-65 of beta-catenin were assayed with purified rat liver CK1 or recombinant CK1 alpha and CK1 alpha L from zebrafish. The results demonstrate that SLS and acidic cluster motifs are crucial for CK1 recognition. Pro-44 and Pro-52 are also important for efficient phosphorylation. Similar results were obtained with the different isoforms of CK1. Phosphorylation of mutants of full-length recombinant beta-catenin from zebrafish confirmed the importance of the SLS and acidic cluster motifs. A search for proteins with similar motifs yielded, among other proteins, adenomatous polyposis coli, previously found to be phosphorylated by CK1. There is a strong correlation of beta-catenin mutations found in thyroid tumors with the motifs recognized by CK1 in this protein.
Marin
Oriano
O
Dipartamento di Chimica Biologica, Universitá di Padova, and Istituto Veneto di Medicina Molecolare, Padova, Italy.
Bustos
Victor H
VH
Cesaro
Luca
L
Meggio
Flavio
F
Pagano
Mario A
MA
Antonelli
Marcelo
M
Allende
Catherine C
CC
Pinna
Lorenzo A
LA
Allende
Jorge E
JE
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D047388:Casein Kinases; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010766:Phosphorylation; D011494:Protein Kinases / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry; D051176:beta Catenin
C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D011494:Protein Kinases; D047388:Casein Kinases; D038362:Glycogen Synthase Kinase 3