Truncated Adenomatous Polyposis Coli Mutation Induces Asef-Activated Golgi Fragmentation

Mol Cell Biol. 2018 Aug 15;38(17):e00135-18. doi: 10.1128/MCB.00135-18. Print 2018 Sep 1.


Adenomatous polyposis coli (APC) is a key molecule to maintain cellular homeostasis in colonic epithelium by regulating cell-cell adhesion, cell polarity, and cell migration through activating the APC-stimulated guanine nucleotide-exchange factor (Asef). The APC-activated Asef stimulates the small GTPase, which leads to decreased cell-cell adherence and cell polarity, and enhanced cell migration. In colorectal cancers, while truncated APC constitutively activates Asef and promotes cancer initiation and progression, regulation of Asef by full-length APC is still unclear. Here, we report the autoinhibition mechanism of full-length APC. We found that the armadillo repeats in full-length APC interact with the APC residues 1362 to 1540 (APC-2,3 repeats), and this interaction competes off and inhibits Asef. Deletion of APC-2,3 repeats permits Asef interactions leading to downstream signaling events, including the induction of Golgi fragmentation through the activation of the Asef-ROCK-MLC2. Truncated APC also disrupts protein trafficking and cholesterol homeostasis by inhibition of SREBP2 activity in a Golgi fragmentation-dependent manner. Our study thus uncovers the autoinhibition mechanism of full-length APC and a novel gain of function of truncated APC in regulating Golgi structure, as well as cholesterol homeostasis, which provides a potential target for pharmaceutical intervention against colon cancers.

Keywords: APC; Asef; Golgi fragmentation; adenomatous polyposis coli; armadillo repeats.

Publication types

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

MeSH terms

  • Adenomatous Polyposis Coli Protein / chemistry
  • Adenomatous Polyposis Coli Protein / genetics*
  • Adenomatous Polyposis Coli Protein / metabolism*
  • Amino Acid Sequence
  • Armadillo Domain Proteins / chemistry
  • Armadillo Domain Proteins / genetics
  • Armadillo Domain Proteins / metabolism
  • Binding Sites
  • Cell Line, Tumor
  • Cell Movement
  • Cholesterol / metabolism
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Gain of Function Mutation*
  • Genes, APC*
  • Golgi Apparatus / metabolism*
  • Golgi Apparatus / pathology
  • HCT116 Cells
  • HT29 Cells
  • Homeostasis
  • Humans
  • Models, Biological
  • Models, Molecular
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • Sequence Deletion
  • Signal Transduction


  • APC protein, human
  • ARHGEF4 protein, human
  • Adenomatous Polyposis Coli Protein
  • Armadillo Domain Proteins
  • Peptide Fragments
  • Rho Guanine Nucleotide Exchange Factors
  • Cholesterol