Control of epithelial cell migration and invasion by the IKKβ- and CK1α-mediated degradation of RAPGEF2

Roberto Magliozzi, Low Teck Yew, Bart G.M.W. Weijts, Tianhong Cheng, Emma Spanjaard, Shabaz Mohammed, Anouk vanVeen, Huib Ovaa, Johan deRooij, Fried J.T. Zwartkruis, Johannes L. Bos, Alain deBruin, Albert J.R. Heck, Daniele Guardavaccaro

Research output: Contribution to journalArticle

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Abstract

Epithelial cell migration is crucial for the development and regeneration of epithelial tissues. Aberrant regulation of epithelial cell migration has a major role in pathological processes such as the development of cancer metastasis and tissue fibrosis. Here, we report that in response to factors that promote cell motility, the Rap guanine exchange factor RAPGEF2 is rapidly phosphorylated by I-kappa-B-kinase-β and casein kinase-1α and consequently degraded by the proteasome via the SCFβTrCP ubiquitin ligase. Failure to degrade RAPGEF2 in epithelial cells results in sustained activity of Rap1 and inhibition of cell migration induced by HGF, a potent metastatic factor. Furthermore, expression of a degradation-resistant RAPGEF2 mutant greatly suppresses dissemination and metastasis of human breast cancer cells. These findings reveal a molecular mechanism regulating migration and invasion of epithelial cells and establish a key direct link between IKKβ and cell motility controlled by Rap-integrinsignaling.

Original languageEnglish
Pages (from-to)574-585
Number of pages12
JournalDevelopmental Cell
Volume27
Issue number5
DOIs
Publication statusPublished - 9 Dec 2013
Externally publishedYes

Fingerprint

Cell Movement
Epithelial Cells
Degradation
I-kappa B Kinase
Casein Kinase I
Cells
Cell Migration Inhibition
Tissue
Neoplasm Metastasis
Guanine
Proteasome Endopeptidase Complex
Pathologic Processes
Ligases
Ubiquitin
Regeneration
Fibrosis
Epithelium
Breast Neoplasms
Neoplasms

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Magliozzi, R., Teck Yew, L., Weijts, B. G. M. W., Cheng, T., Spanjaard, E., Mohammed, S., ... Guardavaccaro, D. (2013). Control of epithelial cell migration and invasion by the IKKβ- and CK1α-mediated degradation of RAPGEF2. Developmental Cell, 27(5), 574-585. https://doi.org/10.1016/j.devcel.2013.10.023

Control of epithelial cell migration and invasion by the IKKβ- and CK1α-mediated degradation of RAPGEF2. / Magliozzi, Roberto; Teck Yew, Low; Weijts, Bart G.M.W.; Cheng, Tianhong; Spanjaard, Emma; Mohammed, Shabaz; vanVeen, Anouk; Ovaa, Huib; deRooij, Johan; Zwartkruis, Fried J.T.; Bos, Johannes L.; deBruin, Alain; Heck, Albert J.R.; Guardavaccaro, Daniele.

In: Developmental Cell, Vol. 27, No. 5, 09.12.2013, p. 574-585.

Research output: Contribution to journalArticle

Magliozzi, R, Teck Yew, L, Weijts, BGMW, Cheng, T, Spanjaard, E, Mohammed, S, vanVeen, A, Ovaa, H, deRooij, J, Zwartkruis, FJT, Bos, JL, deBruin, A, Heck, AJR & Guardavaccaro, D 2013, 'Control of epithelial cell migration and invasion by the IKKβ- and CK1α-mediated degradation of RAPGEF2', Developmental Cell, vol. 27, no. 5, pp. 574-585. https://doi.org/10.1016/j.devcel.2013.10.023
Magliozzi, Roberto ; Teck Yew, Low ; Weijts, Bart G.M.W. ; Cheng, Tianhong ; Spanjaard, Emma ; Mohammed, Shabaz ; vanVeen, Anouk ; Ovaa, Huib ; deRooij, Johan ; Zwartkruis, Fried J.T. ; Bos, Johannes L. ; deBruin, Alain ; Heck, Albert J.R. ; Guardavaccaro, Daniele. / Control of epithelial cell migration and invasion by the IKKβ- and CK1α-mediated degradation of RAPGEF2. In: Developmental Cell. 2013 ; Vol. 27, No. 5. pp. 574-585.
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