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The subcellular destinations of apc proteins

Nature Reviews Molecular Cell Biology volume 3, pages 328–338 (2002)Cite this article

Key Points

  • APC proteins are well-conserved antagonists of canonical Wnt signalling with crucial functions in normal and malignant development.

  • The classical function of APC proteins is to promote the destabilization of β-catenin–Armadillo in the cytoplasm, probably by binding to the Axin destruction complex.

  • A highly conserved nuclear-export function of APC proteins seems to be crucial for their ability to downregulate the activity of nuclear β-catenin–Armadillo.

  • APC proteins are also associated with the plasma membrane of epithelial cells where they ensure the maintainance of adherens junctions and, perhaps indirectly, the orientation of mitotic spindles in the epithelial plane.

  • The ability of APC to cluster at growing microtubule plus ends might affect the migratory behaviour of motile cells.

  • Chromosomal non-disjunction might result from a failure of mutant APC to bind to microtubule plus ends of mitotic spindles which, in turn, might cause a failure of microtubule capture by kinetochores or by the cell cortex.

  • The shuttling of APC between the different subcellular compartments and its control vary between different cell types and states.

  • The ultimate question is whether APC proteins have a single molecular function that underlies its many cellular functions — which are apparently disparate from each other — and manifest themselves in various biological contexts.

Abstract

Adenomatous polyposis coli (APC) is an important tumour suppressor in the human colon, and is conserved in various organisms. Its best understood function is the destabilization of β-catenin, a key effector of the Wnt signalling pathway. APC proteins are highly motile, and shuttle between several subcellular destinations. These destinations have prompted the discovery of new functions for the APC proteins, and this multitasking of APC might explain why its loss often leads to cancer.

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Figure 1: APC proteins and the mutation cluster region.
Figure 2: The Wnt signalling pathway.
Figure 3: The different subcellular pools of APC proteins.
Figure 4: APC and the cortical capture of microtubules.

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Acknowledgements

I thank R. Rosin-Arbesfeld and A. Cliffe for providing images and supplementary material. I am also grateful to many colleagues for stimulating discussions, in particular I. Näthke, A. Venkitaraman, P. Edwards and S. Taylor. Finally, I apologize to colleagues to whose work I have not referred due to space constraints.

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  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

    Mariann Bienz

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DATABASES

Flybase

dAPC

APC2

Armadillo

Arrow

CRM1

dEB1

Frizzled

Interpro

ARD

LocusLink

Axin

Bub1

Conductin

OMIM

familial adenomatous polyposis

<i>Saccharomyces</i> Genome Database

Bim1

Kar9

Swiss-Prot

APC

APCL

Asef

β-catenin

Bub3

Cdc2

CKIɛ

GFP

GSK-3β

p53

TCF

FURTHER INFORMATION

Wnt web site

APC mutation database

Glossary

CRYPT

Stem-cell compartment in the mammalian intestinal epithelium.

CADHERIN

Calcium-dependent adhesion molecules that mediate homophilic adhesions. There are several subfamilies of cadherin.

PROTEASOME

A large multisubunit protease complex that selectively degrades intracellular proteins. Targeting to proteasomes most often occurs through attachment of polyubiquitin tags.

FRIZZLED

A protein family of seven-transmembrane receptors. Its founding member, frizzled, was identified as a so-called tissue-polarity mutation in Drosophila that causes defects in the orientation of bristles and hairs. Frizzled proteins function as receptors for Wingless and its vertebrate homologues, the Wnt proteins.

PLANAR POLARITY

The polarity of cells in the plane of an epithelium.

FRET

A technique in which a fluorophore donor molecule is excited and transfers the energy of an adsorbed photon to an acceptor molecule. This technique can be used to study protein–protein interactions.

ARMADILLO REPEAT DOMAIN

(ARD) A sequence of ∼42 amino acids repeated in tandem, which was first identified in the Drosophila segment-polarity gene armadillo. The structure of this domain is known.

NUCLEOPORINS

Proteins that mediate nuclear transport in cooperation with karyopherins, a GTPase and Ran.

INTERPHASE

The period between two mitotic divisions.

ADHERENS JUNCTION

A cell–cell adhesion complex that is composed of cadherins that are attached to cytoplasmic actin filaments by catenins.

ASTRAL MICROTUBULES

The microtubules of mitotic spindles that do not attach to chromosomes, but point to the cell cortex. In yeast, these are called cytoplasmic microtubules.

FOCAL ADHESIONS

Cellular structures that link the extracellular matrix on the outside of the cell, by integrin receptors, to the actin cytoskeleton inside the cell.

GEF

All members of the Ras superfamily of GTPases cycle between a GTP- and a GDP-bound state. After GTP hydrolysis (usually facilitated by a GTPase-activating protein or GAP), exchange factors (GEFs) facilitate release of the GDP and binding of the more abundant GTP.

LAMELLIPODIA

Thin sheet-like cell extensions found at the leading edge of crawling cells or growth cones.

CENTROSOMES

The main microtubule-organizing centre of animal cells. In yeast, this is known as the spindle-pole body.

KINETOCHORE

A structure that connects each chromatid to the spindle microtubules, which shorten as pairs of chromatids are separated to opposite poles.

ANEUPLOID

The ploidy of a cell refers to the number of sets of chromosomes that it contains. Aneuploid karyotypes are those in which the chromosome complements are not a simple multiple of the haploid set.

SPINDLE CHECKPOINT

A highly conserved surveillance mechanism in mitosis and meiosis that minimizes chromosome loss by preventing chromosomes from initiating anaphase until all kinetochores have successfully captured spindle microtubules.

ALLELIC IMBALANCE

Refers to local aneuploidy, whereby the number of a given gene or allele deviates from 2n (diploidy).

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Bienz, M. The subcellular destinations of apc proteins. Nat Rev Mol Cell Biol 3, 328–338 (2002). https://doi.org/10.1038/nrm806

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