A noncanonical sequence phosphorylated by casein kinase 1 in β-catenin may play a role in casein kinase 1 targeting of important signaling proteins

Abstract

Protein kinase casein kinase 1 (CK1) phosphorylates Ser-45 of ␤-catenin, ''priming'' the subsequent phosphorylation by glycogen synthase-3 of residues 41, 37, and 33. This concerted phosphorylation of ␤-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 ␤-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 ␤-catenin were assayed with purified rat liver CK1 or recombinant CK1␣ and CK1␣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 ␤-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 ␤-catenin mutations found in thyroid tumors with the motifs recognized by CK1 in this protein.consensus sequence ͉ nuclear factor for activated T cells 4 ͉ adenomatous polyposis coli ͉ Wnt signaling ͉ thyroid tumor mutations

Phosphorylation of nm23-H1 by CKI induces its complex formation with h-prune and promotes cell motility

“…The spectral analysis revealed another doubly charged (2 þ ) signal at m/z 823.27, identified as the same 115-128 peptide that was modified with two phosphate groups at levels of both S122 and S125, with no modifications seen on S120. The phosphomodification on S122 occurs outside of the consensus sequence, a phenomenon that has been described for other casein kinase substrates (Marin et al, 1994(Marin et al, , 2003.…”

DNA Damage Induces the Accumulation of Tiam1 by Blocking β-TrCP-dependent Degradation

“…Hence, we decided to identify the specific kinases responsible for Tiam1 phosphorylation that led to ␤-TrCP recognition. Analysis of the amino acid sequence in Tiam1 revealed many serine and threonine residues coincident with CK1 consensus phosphorylation motifs, D/EXXS and S/T-PO 4 XXS/T (42). Therefore, we performed a coimmunoprecipitation assay and found that Tiam1 interacted predominantly with CK1␦ and CK1⑀, whereas its interaction with CK1␣ was much weaker and, with CK1␥, undetectable ( Fig.…”

The -Catenin Destruction Complex

“…CK1 initially phosphorylates Ser45 of b-catenin (Amit et al 2002;Liu et al 2002), and is targeted to this site by a cluster of acidic residues located seven amino acids carboxy-terminally ( Fig. 1) (Marin et al 2003). GSK-3 phosphorylates residues in the sequence S/T-X-X-X-pS/pT, in which the bold residue represents the phosphorylation site, and X is any amino acid (Fiol et al 1987;.…”