The adenomatous polyposis coli tumor suppressor protein localizes to plasma membrane sites involved in active cell migration.

Mutations in the adenomatous polyposis coli (APC) gene are linked to polyp formation in familial and sporadic colon cancer, but the functions of the protein are not known. We show that APC protein localizes mainly to clusters of puncta near the ends of microtubules that extend into actively migrating regions of epithelial cell membranes. This subcellular distribution of APC protein requires microtubules, but not actin filaments. APC protein-containing membranes are actively involved in cell migration in response to wounding epithelial monolayers, addition of the motorgen hepatocyte growth factor, and during the formation of cell-cell contacts. In the intestine, APC protein levels increase at the crypt/villus boundary, where cell migration is crucial for enterocyte exit from the crypt and where cells accumulate during polyp formation that is linked to mutations in the microtubule-binding domain of APC protein. Together, these data indicate that APC protein has a role in directed cell migration.

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Adenomatous polyposis coli (APC) protein regulates epithelial cell migration and morphogenesis via PDZ domain-based interactions with plasma membranes

Genes to Cells ◽

10.1111/j.1365-2443.2007.01045.x ◽

2007 ◽

Vol 12 (2) ◽

pp. 219-233 ◽

Cited By ~ 23

Author(s):

Yuko Mimori-Kiyosue ◽

Chiyuki Matsui ◽

Hiroyuki Sasaki ◽

Shoichiro Tsukita

Keyword(s):

Cell Migration ◽

Epithelial Cell ◽

Adenomatous Polyposis Coli ◽

Plasma Membranes ◽

Pdz Domain ◽

Adenomatous Polyposis ◽

Polyposis Coli ◽

Epithelial Cell Migration ◽

Apc Protein

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Adenomatous polyposis coli nucleates actin assembly to drive cell migration and microtubule-induced focal adhesion turnover

The Journal of Cell Biology ◽

10.1083/jcb.201702007 ◽

2017 ◽

Vol 216 (9) ◽

pp. 2859-2875 ◽

Cited By ~ 34

Author(s):

M. Angeles Juanes ◽

Habib Bouguenina ◽

Julian A. Eskin ◽

Richa Jaiswal ◽

Ali Badache ◽

...

Keyword(s):

Cell Migration ◽

Adenomatous Polyposis Coli ◽

Focal Adhesions ◽

Adenomatous Polyposis ◽

Actin Assembly ◽

Polyposis Coli ◽

Directed Cell Migration ◽

Direct Cell ◽

Mitochondrial Distribution

Cell motility depends on tight coordination between the microtubule (MT) and actin cytoskeletons, but the mechanisms underlying this MT–actin cross talk have remained poorly understood. Here, we show that the tumor suppressor protein adenomatous polyposis coli (APC), which is a known MT-associated protein, directly nucleates actin assembly to promote directed cell migration. By changing only two residues in APC, we generated a separation-of-function mutant, APC (m4), that abolishes actin nucleation activity without affecting MT interactions. Expression of full-length APC carrying the m4 mutation (APC (m4)) rescued cellular defects in MT organization, MT dynamics, and mitochondrial distribution caused by depletion of endogenous APC but failed to restore cell migration. Wild-type APC and APC (m4) localized to focal adhesions (FAs), and APC (m4) was defective in promoting actin assembly at FAs to facilitate MT-induced FA turnover. These results provide the first direct evidence for APC-mediated actin assembly in vivo and establish a role for APC in coordinating MTs and actin at FAs to direct cell migration.

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Lack of Adenomatous Polyposis Coli Protein Correlates with a Decrease in Cell Migration and Overall Changes in Microtubule Stability

Molecular Biology of the Cell ◽

10.1091/mbc.e06-03-0179 ◽

2007 ◽

Vol 18 (3) ◽

pp. 910-918 ◽

Cited By ~ 80

Author(s):

Karin Kroboth ◽

Ian P. Newton ◽

Katsuhiro Kita ◽

Dina Dikovskaya ◽

Jürg Zumbrunn ◽

...

Keyword(s):

Cell Migration ◽

Adenomatous Polyposis Coli ◽

Cell Periphery ◽

Adenomatous Polyposis ◽

Polyposis Coli ◽

Adenomatous Polyposis Coli Protein ◽

Therapeutic Implications ◽

Microtubule Stability ◽

Apc Protein ◽

Direct And Indirect Binding

Most sporadic colorectal tumors carry truncation mutations in the adenomatous polyposis coli (APC) gene. The APC protein is involved in many processes that govern gut tissue. In addition to its involvement in the regulation of β-catenin, APC is a cytoskeletal regulator with direct and indirect effects on microtubules. Cancer-related truncation mutations lack direct and indirect binding sites for microtubules in APC, suggesting that loss of this function contributes to defects in APC-mutant cells. In this study, we show that loss of APC results in disappearance of cellular protrusions and decreased cell migration. These changes are accompanied by a decrease in overall microtubule stability and also by a decrease in posttranslationally modified microtubules in the cell periphery particularly the migrating edge. Consistent with the ability of APC to affect cell shape, the overexpression of APC in cells can induce cellular protrusions. These data demonstrate that cell migration and microtubule stability are linked to APC status, thereby revealing a weakness in APC-deficient cells with potential therapeutic implications.

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The Adenomatous Polyposis Coli Protein Is Required for the Formation of Robust Spindles Formed in CSF Xenopus Extracts

Molecular Biology of the Cell ◽

10.1091/mbc.e03-08-0613 ◽

2004 ◽

Vol 15 (6) ◽

pp. 2978-2991 ◽

Cited By ~ 52

Author(s):

Dina Dikovskaya ◽

Ian P. Newton ◽

Inke S. Näthke

Keyword(s):

Adenomatous Polyposis Coli ◽

Chromosomal Instability ◽

Adenomatous Polyposis ◽

Mitotic Spindles ◽

Polyposis Coli ◽

Adenomatous Polyposis Coli Protein ◽

Microtubule Binding ◽

Microtubule Polymerization ◽

Large N ◽

Apc Protein

Mutations in the adenomatous polyposis coli (APC) protein occur early in colon cancer and correlate with chromosomal instability. Here, we show that depletion of APC from cystostatic factor (CSF) Xenopus extracts leads to a decrease in microtubule density and changes in tubulin distribution in spindles and asters formed in such extracts. Addition of full-length APC protein or a large, N-terminally truncated APC fragment to APC-depleted extracts restored normal spindle morphology and the intact microtubule-binding site of APC was necessary for this rescue. These data indicate that the APC protein plays a role in the formation of spindles that is dependent on its effect on microtubules. Spindles formed in cycled extracts were not sensitive to APC depletion. In CSF extracts, spindles predominantly formed from aster-like intermediates, whereas in cycled extracts chromatin was the major site of initial microtubule polymerization. These data suggest that APC is important for centrosomally driven spindle formation, which was confirmed by our finding that APC depletion reduced the size of asters nucleated from isolated centrosomes. We propose that lack of microtubule binding in cancer-associated mutations of APC may contribute to defects in the assembly of mitotic spindles and lead to missegregation of chromosomes.

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Evidence for the involvement of adenomatous polyposis coli (APC) protein in maintaining cellular distributions of α3β4 nicotinic receptors

Neuroscience Letters ◽

10.1016/j.neulet.2010.11.075 ◽

2011 ◽

Vol 489 (2) ◽

pp. 105-109

Author(s):

Tulaya Potaros ◽

Srichan Phornchirasilp ◽

Susan B. McKay ◽

Tatiana F. González-Cestari ◽

R. Thomas Boyd ◽

...

Keyword(s):

Adenomatous Polyposis Coli ◽

Nicotinic Receptors ◽

Adenomatous Polyposis ◽

Polyposis Coli ◽

Apc Protein

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Truncated Adenomatous Polyposis Coli Mutation Induces Asef-Activated Golgi Fragmentation

Molecular and Cellular Biology ◽

10.1128/mcb.00135-18 ◽

2018 ◽

Vol 38 (17) ◽

Cited By ~ 5

Author(s):

Sang Bum Kim ◽

Lu Zhang ◽

Jimok Yoon ◽

Jeon Lee ◽

Jaewon Min ◽

...

Keyword(s):

Cell Migration ◽

Cell Polarity ◽

Adenomatous Polyposis Coli ◽

Full Length ◽

Cholesterol Homeostasis ◽

Dependent Manner ◽

Adenomatous Polyposis ◽

Polyposis Coli ◽

Golgi Fragmentation ◽

Cell Cell

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.

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