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 language | English |
|---|---|
| Pages (from-to) | 574-585 |
| Number of pages | 12 |
| Journal | Developmental Cell |
| Volume | 27 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 9 Dec 2013 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Developmental Biology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Control of epithelial cell migration and invasion by the IKKβ- and CK1α-mediated degradation of RAPGEF2
AU - Magliozzi, Roberto
AU - Teck Yew, Low
AU - Weijts, Bart G.M.W.
AU - Cheng, Tianhong
AU - Spanjaard, Emma
AU - Mohammed, Shabaz
AU - vanVeen, Anouk
AU - Ovaa, Huib
AU - deRooij, Johan
AU - Zwartkruis, Fried J.T.
AU - Bos, Johannes L.
AU - deBruin, Alain
AU - Heck, Albert J.R.
AU - Guardavaccaro, Daniele
PY - 2013/12/9
Y1 - 2013/12/9
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84892370124&partnerID=8YFLogxK
U2 - 10.1016/j.devcel.2013.10.023
DO - 10.1016/j.devcel.2013.10.023
M3 - Article
VL - 27
SP - 574
EP - 585
JO - Developmental Cell
JF - Developmental Cell
SN - 1534-5807
IS - 5
ER -