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Truncated Adenomatous Polyposis Coli Mutation Induces Asef-Activated Golgi Fragmentation

Authors
 Sang Bum Kim  ;  Lu Zhang  ;  Jimok Yoon  ;  Jeon Lee  ;  Jaewon Min  ;  Wenlin Li  ;  Nick V. Grishin  ;  Young-Ah Moon  ;  Woodring E. Wright  ;  Jerry W. Shay 
Citation
 MOLECULAR AND CELLULAR BIOLOGY, Vol.38(17) : e00135-18, 2018 
Journal Title
MOLECULAR AND CELLULAR BIOLOGY
ISSN
 0270-7306 
Issue Date
2018
Keywords
APC ; Asef ; Golgi fragmentation ; adenomatous polyposis coli ; armadillo repeats
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.
DOI
10.1128/MCB.00135-18
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Sang Bum(김상범) ORCID logo https://orcid.org/0000-0001-5965-3354
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/167487
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