The adenomatous polyposis coli protein: in the limelight out at the edge

doi:10.1016/S0962-8924(01)02069-4

Trends in Cell Biology

Volume 11, Issue 9, 1 September 2001, Pages 378-384

https://doi.org/10.1016/S0962-8924(01)02069-4 Get rights and content

Abstract

Truncation mutations in the adenomatous polyposis coli protein (APC) are responsible for familial and sporadic colonic tumours. APC is best known for its role in regulating β-catenin, an important mediator of cell adhesion and a transcriptional activator. However, recent studies indicate that APC has additional roles in cytoskeletal regulation. It binds to microtubules directly and indirectly. Furthermore, indirect connections between APC and the actin cytoskeleton have also been described. Here, we integrate recent information describing the association between APC and the cytoskeleton to illustrate how this multifaceted protein might link different cytoskeletal elements to each other and to cellular signaling pathways.

Section snippets

APC proteins

APC and related proteins have been identified in a number of vertebrate species, Drosophila melanogaster and Caenorhabditis elegans 7, 8, 9. In mouse, APC and APC-2 have been identified 10, 11, and in humans, APC and APC-L have been described correspondingly 12, 13 (APC-2 and APC-L will be referred to as APC-2/L because they are highly related) (Fig. 1). In Drosophila there are also two forms of APC: D-APC and E-APC 7, 14, 15. All identified APC proteins can function in Wnt signaling but

Roles for APC outside the Wnt signaling pathway?

Although many effects of inactivating APC are explained by its role in the Wnt signaling pathway, some observations in tissues and animals lacking APC indicate that APC has additional functions related to its ability to interact with the cytoskeleton. This idea is further supported by the presence of domains in the APC molecule that mediate the interactions of APC with a number of proteins not involved in Wnt signaling (Fig. 1). Mice heterozygous for truncated APC (either APC^min, truncated

APC binds to microtubules

The interaction of APC with the tubulin cytoskeleton was recognized some time ago 32, 33 but until recently relatively few studies have focused on this aspect of APC function. Biochemical studies on the interaction of APC and microtubules revealed that a 200-amino acid region rich in positively charged amino acids in the C-terminal third of the molecule binds microtubules and induces microtubule bundling in vitro ³⁴. GTP hydrolysis by tubulin was not affected when this domain was bound to

The interaction of APC with microtubules is complex

A possible explanation for the unique interaction of APC with microtubules might be the presence of multiple binding sites for microtubules and microtubule-binding proteins (Fig. 1). In addition to the basic domain in the C-terminal third of APC that binds to microtubules directly (see above), APC contains a binding site for EB1, another microtubule-binding protein 38, 39. APC lacking the basic domain still associates with microtubules, and the isolated domain of 200 amino acids rich in

APC in mitosis

Another important function for microtubules is the formation of mitotic spindles that mediate chromosome segregation during mitosis. A role for APC as a microtubule-binding protein in mitosis has recently been suggested. APC localizes to the external face of kinetochores where microtubules attach to chromosomes 43, 44 (Fig. 3b). This localization combined with the ability of APC to stabilize microtubules, suggested that APC has a role in microtubule attachment and/or stabilization at

APC interactions with actin

In addition to association with microtubules, APC might also be connected to the actin cytoskeleton. Such an interaction is likely to be indirect and could be mediated by a number of known APC-binding partners. β-Catenin could establish an indirect connection between APC and actin by providing a bridge to α-catenin, which can bind to actin directly ⁶⁰ (Fig. 4). However, such interaction is predicted to be short-lived as β-catenin bound to APC is targeted for rapid degradation. In addition, the

APC as a cytoskeletal linker protein

Endogenous APC localizes mainly to the tubulin cytoskeleton in vertebrate cells; however, when this interaction is disrupted, APC can associate with actin. In nocodazole-treated cells, APC clusters that are released from destabilized microtubule ends align with actin filaments and move with the actin cytoskeleton ¹⁹. This shows that the APC molecule is able to interact with both actin and tubulin. Which cytoskeletal element is favoured by a particular APC protein must then depend on the

Concluding remarks

Recent work shows that APC proteins are potential regulators of cytoskeletal dynamics that could link different cytoskeletal elements and important signaling pathways. This places APC in a unique position at the intersection between diverse pathways in line with its proposed role as a ‘gatekeeper’ ⁶⁵. The effects of APC mutations on multiple stages of tumour development might help to explain the high penetrance of APC mutations. Impaired cell migration due to loss of APC might promote the

Acknowledgements

We thank Jennifer Tirnauer and Elizabeth Smythe for helpful comments on the manuscript. I.S.N. is supported by a Cancer Research Senior Fellowship and a Career Development award in the Biomedical Sciences from the Burroughs Wellcome Fund.

References (69)

P. Polakis
More than one way to skin a catenin
Cell
(2001)
K. Orford
Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin
J. Biol. Chem.
(1997)
M. Bienz et al.
Linking colorectal cancer to Wnt signaling
Cell
(2000)
C.E. Rocheleau
Wnt signaling and an APC-related gene specify endoderm in early C. elegans embryos
Cell
(1997)
C.J. Thorpe
Wnt signalling polarizes an early C. elegans blastomere to distinguish endoderm from mesoderm
Cell
(1997)
C.L. Day et al.
Crystal structure of the amino-terminal coiled-coil domain of the APC tumor suppressor
J. Mol. Biol.
(2000)
S.F. Moss
Inward growth of colonic adenomatous polyps
Gastroenterology
(1996)
J. Zumbrunn
Binding of the Adenomatous Polyposis Coli protein to microtubules increases microtubule stability and is regulated by GSK3β phosphorylation
Curr. Biol.
(2001)
Y. Mimori-Kiyosue
The dynamic behavior of the APC-binding protein EB1 on the distal ends of microtubules
Curr. Biol.
(2000)
D.L. Beach
The role of the proteins Kar9 and Myo2 in orienting the mitotic spindle of budding yeast
Curr. Biol.
(2000)

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Trends in Cell Biology

ReviewThe adenomatous polyposis coli protein: in the limelight out at the edge

Abstract

Section snippets

APC proteins

Roles for APC outside the Wnt signaling pathway?

APC binds to microtubules

The interaction of APC with microtubules is complex

APC in mitosis

APC interactions with actin

APC as a cytoskeletal linker protein

Concluding remarks

Acknowledgements

Cell

J. Biol. Chem.

Cell

Cell

Cell

J. Mol. Biol.

Gastroenterology

Curr. Biol.

Curr. Biol.

Curr. Biol.

Mech. Dev.

Curr. Biol.

J. Biol. Chem.

Curr. Biol.

Trends Cell Biol.

J. Biol. Chem.

Curr. Biol.

The abc of apc

Hum. Mol. Genet.

Beta-catenin is a target for the ubiquitin-proteasome pathway

EMBO J.

Wnt signaling and cancer

Genes Dev.

A Drosophila homolog of the tumor suppressor gene adenomatous polyposis coli down-regulates beta-catenin but its zygotic expression is not essential for the regulation of Armadillo

Proc. Natl. Acad. Sci. U. S. A.

Multiple intestinal neoplasia caused by mutations in the murine homolog of the APC gene

Science

Identification of APC2, a homologue of the adenomatous polyposis coli tumour suppressor

Curr. Biol.

Identification of FAP locus genes from chromosome 5q21

Science

Identification of a brain-specific APC homologue, APCL, and its interaction with β-catenin

Cancer Res.

Drosophila APC2 is a cytoskeletally-associated protein that regulates Wnt signaling in the embryonic epidermis

J. Cell Biol.

A new Drosophila APC homologue associated with adhesive zones of epithelial cells

Nat. Cell Biol.

Dimer formation by an N-terminal coiled coil in the APC protein

Proc. Natl. Acad. Sci. U. S. A.

Predicting coiled coils from protein sequences

Science

Adenomatous Polyposis Coli (APC) protein moves along microtubules and concentrates at their growing ends in epithelial cells

J. Cell Biol.

Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development

Genes Dev.

Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A

Science

Asef, a link between the tumor suppressor APC and G-protein signaling

Science

Regulation and function of the interaction between the APC tumour suppressor protein and EB1

Oncogene

Review
The adenomatous polyposis coli protein: in the limelight out at the edge