Phosphorylation-dependent interaction between tumor suppressors Dlg and Lgl

Cell Res. 2014 Apr;24(4):451-63. doi: 10.1038/cr.2014.16. Epub 2014 Feb 11.

Abstract

The tumor suppressors Discs Large (Dlg), Lethal giant larvae (Lgl) and Scribble are essential for the establishment and maintenance of epithelial cell polarity in metazoan. Dlg, Lgl and Scribble are known to interact strongly with each other genetically and form the evolutionarily conserved Scribble complex. Despite more than a decade of extensive research, it has not been demonstrated whether Dlg, Lgl and Scribble physically interact with each other. Here, we show that Dlg directly interacts with Lgl in a phosphorylation-dependent manner. Phosphorylation of any one of the three conserved Ser residues situated in the central linker region of Lgl is sufficient for its binding to the Dlg guanylate kinase (GK) domain. The crystal structures of the Dlg4 GK domain in complex with two phosphor-Lgl2 peptides reveal the molecular mechanism underlying the specific and phosphorylation-dependent Dlg/Lgl complex formation. In addition to providing a mechanistic basis underlying the regulated formation of the Scribble complex, the structure of the Dlg/Lgl complex may also serve as a starting point for designing specific Dlg inhibitors for targeting the Scribble complex formation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites / genetics
  • Cell Polarity / genetics
  • Crystallography, X-Ray
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Disks Large Homolog 4 Protein
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein Interaction Domains and Motifs / genetics
  • Protein Kinase C / metabolism*
  • Protein Structure, Quaternary
  • Rats
  • Sequence Homology, Amino Acid
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • Cytoskeletal Proteins
  • DLG4 protein, human
  • Disks Large Homolog 4 Protein
  • Hugl-2 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Tumor Suppressor Proteins
  • Protein Kinase C