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

Truncated Adenomatous Polyposis Coli Mutation Induces Asef-Activated Golgi Fragmentation.

Author information

1
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA ksbom1@yuhs.ac jerry.shay@utsouthwestern.edu.
2
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
4
Department of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
5
Department of Molecular Medicine, Inha University College of Medicine, Nam-gu, Incheon, Republic of Korea.
#
Contributed equally

Abstract

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

PMID:
29866653
PMCID:
PMC6094051
DOI:
10.1128/MCB.00135-18
[Indexed for MEDLINE]
Free PMC Article

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