CDK1-mediated BCL9 phosphorylation inhibits clathrin to promote mitotic Wnt signalling

EMBO J. 2018 Oct 15;37(20):e99395. doi: 10.15252/embj.201899395. Epub 2018 Sep 14.

Abstract

Uncontrolled cell division is a hallmark of cancer. Deregulation of Wnt components has been linked to aberrant cell division by multiple mechanisms, including Wnt-mediated stabilisation of proteins signalling, which was notably observed in mitosis. Analysis of Wnt components revealed an unexpected role of B-cell CLL/lymphoma 9 (BCL9) in maintaining mitotic Wnt signalling to promote precise cell division and growth of cancer cell. Mitotic interactome analysis revealed a mechanistic role of BCL9 in inhibiting clathrin-mediated degradation of LRP6 signalosome components by interacting with clathrin and the components in Wnt destruction complex; this function was further controlled by CDK1-driven phosphorylation of BCL9 N-terminal, especially T172. Interestingly, T172 phosphorylation was correlated with cancer patient prognosis and enriched in tumours. Thus, our results revealed a novel role of BCL9 in controlling mitotic Wnt signalling to promote cell division and growth.

Keywords: BCL9; BCL9 phosphorylation; CDK1; Wnt signalling; cell division; clathrin; mitosis; spindle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2 Protein Kinase / metabolism*
  • Clathrin / metabolism*
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
  • Mitosis*
  • Neoplasm Proteins / metabolism*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Phosphorylation
  • Protein Domains
  • Transcription Factors
  • Wnt Signaling Pathway*

Substances

  • BCL9 protein, human
  • Clathrin
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Neoplasm Proteins
  • Transcription Factors
  • CDC2 Protein Kinase
  • CDK1 protein, human