Adenomatous polyposis coli protein contains two nuclear export signals and shuttles between the nucleus and cytoplasm

Kristi L. Neufeld, David A. Nix, Hal Bogerd, Yibin Kang, Mary C. Beckerle, Bryan R. Cullen, Raymond L. White

Research output: Contribution to journalArticle

138 Scopus citations

Abstract

Mutational inactivation of the adenomatous polyposis coli (APC) tumor suppressor initiates most hereditary and sporadic colon carcinomas. Although APC protein is located in both the cytoplasm and the nucleus, the protein domains required to maintain a predominantly cytoplasmic localization are unknown. Here, we demonstrate that nuclear export of APC is mediated by two intrinsic, leucine-rich, nuclear export signals (NESs) located near the amino terminus. Each NES was able to induce the nuclear export of a fused carrier protein. Both APC NESs were independently able to interact with the Crm1 nuclear export factor and substitute for the HIV-1 Rev NES to mediate nuclear mRNA export. Both APC NESs functioned within the context of APC sequence: an amino-terminal APC peptide containing both NESs interacted with Crm1 and showed nuclear export in a heterokaryon nucleocytoplasmic shuttling assay. Also, mutation of both APC NESs resulted in the nuclear accumulation of the full-length, ~320-kDa APC protein, further establishing that the two intrinsic APC NESs are necessary for APC protein nuclear export. Moreover, endogenous APC accumulated in the nucleus of cells treated with the Crm1-specific nuclear export inhibitor leptomycin B. Together, these data indicate that APC is a nucleocytoplasmic shuttle protein whose predominantly cytoplasmic localization requires NES function and suggests that APC may be important for signaling between the nuclear and cytoplasmic compartments of epithelial cells.

Original languageEnglish (US)
Pages (from-to)12085-12090
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number22
DOIs
StatePublished - Oct 24 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

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