Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Nat Cell Biol
2010 Mar 01;123:278-85. doi: 10.1038/ncb2028.
Show Gene links
Show Anatomy links
Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex.
Ishitani T
,
Hirao T
,
Suzuki M
,
Isoda M
,
Ishitani S
,
Harigaya K
,
Kitagawa M
,
Matsumoto K
,
Itoh M
.
???displayArticle.abstract???
The Notch signalling pathway has a crucial function in determining cell fates in multiple tissues within metazoan organisms. On binding to ligands, the Notch receptor is cleaved proteolytically and releases its intracellular domain (NotchICD). The NotchICD enters the nucleus and acts cooperatively with other factors to stimulate the transcription of target genes. High levels of Notch-mediated transcriptional activation require the formation of a ternary complex consisting of NotchICD, CSL (CBF-1, suppressor of hairless, LAG-1) and a Mastermind family member. However, it is still not clear how the formation of the ternary complex is regulated. Here we show that Nemo-like kinase (NLK) negatively regulates Notch-dependent transcriptional activation by decreasing the formation of this ternary complex. Using a biochemical screen, we identified Notch as a new substrate of NLK. NLK-phosphorylated Notch1ICD is impaired in its ability to form a transcriptionally active ternary complex. Furthermore, knockdown of NLK leads to hyperactivation of Notch signalling and consequently decreases neurogenesis in zebrafish. Our results both define a new function for NLK and reveal a previously unidentified mode of regulation in the Notch signalling pathway.
Artavanis-Tsakonas,
Notch signaling: cell fate control and signal integration in development.
1999, Pubmed
Artavanis-Tsakonas,
Notch signaling: cell fate control and signal integration in development.
1999,
Pubmed
Bigas,
Notch1 and Notch2 inhibit myeloid differentiation in response to different cytokines.
1998,
Pubmed
Bray,
Notch signalling: a simple pathway becomes complex.
2006,
Pubmed
Choi,
Rotation of photoreceptor clusters in the developing Drosophila eye requires the nemo gene.
1994,
Pubmed
Hyodo-Miura,
Involvement of NLK and Sox11 in neural induction in Xenopus development.
2002,
Pubmed
,
Xenbase
Inglés-Esteve,
Phosphorylation of Ser2078 modulates the Notch2 function in 32D cell differentiation.
2001,
Pubmed
Ishitani,
Regulation of lymphoid enhancer factor 1/T-cell factor by mitogen-activated protein kinase-related Nemo-like kinase-dependent phosphorylation in Wnt/beta-catenin signaling.
2003,
Pubmed
Ishitani,
The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF.
1999,
Pubmed
,
Xenbase
Kanei-Ishii,
Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK.
2004,
Pubmed
Kankel,
Investigating the genetic circuitry of mastermind in Drosophila, a notch signal effector.
2007,
Pubmed
Kim,
Zebrafish elav/HuC homologue as a very early neuronal marker.
1996,
Pubmed
Kitagawa,
A human protein with sequence similarity to Drosophila mastermind coordinates the nuclear form of notch and a CSL protein to build a transcriptional activator complex on target promoters.
2001,
Pubmed
Kojima,
STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGFbeta-activated kinase 1 for STAT3 Ser-727 phosphorylation.
2005,
Pubmed
Kortenjann,
Abnormal bone marrow stroma in mice deficient for nemo-like kinase, Nlk.
2001,
Pubmed
Kurooka,
Functional interaction between the mouse notch1 intracellular region and histone acetyltransferases PCAF and GCN5.
2000,
Pubmed
Kurooka,
Roles of the ankyrin repeats and C-terminal region of the mouse notch1 intracellular region.
1998,
Pubmed
Lin,
Identification of new human mastermind proteins defines a family that consists of positive regulators for notch signaling.
2002,
Pubmed
Meneghini,
MAP kinase and Wnt pathways converge to downregulate an HMG-domain repressor in Caenorhabditis elegans.
1999,
Pubmed
Minoguchi,
RBP-L, a transcription factor related to RBP-Jkappa.
1997,
Pubmed
Mizutani,
Conservation of the biochemical mechanisms of signal transduction among mammalian Notch family members.
2001,
Pubmed
Ohkawara,
Role of the TAK1-NLK-STAT3 pathway in TGF-beta-mediated mesoderm induction.
2004,
Pubmed
,
Xenbase
Oyama,
Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo.
2007,
Pubmed
Pufall,
Variable control of Ets-1 DNA binding by multiple phosphates in an unstructured region.
2005,
Pubmed
Raya,
Notch activity induces Nodal expression and mediates the establishment of left-right asymmetry in vertebrate embryos.
2003,
Pubmed
Shimizu,
Functional diversity among Notch1, Notch2, and Notch3 receptors.
2002,
Pubmed
Takke,
her4, a zebrafish homologue of the Drosophila neurogenic gene E(spl), is a target of NOTCH signalling.
1999,
Pubmed
,
Xenbase
Thorpe,
nemo-like kinase is an essential co-activator of Wnt signaling during early zebrafish development.
2004,
Pubmed
Verheyen,
Analysis of dominant enhancers and suppressors of activated Notch in Drosophila.
1996,
Pubmed
Wettstein,
The Xenopus homolog of Drosophila Suppressor of Hairless mediates Notch signaling during primary neurogenesis.
1997,
Pubmed
,
Xenbase
Wu,
MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors.
2000,
Pubmed
Yeo,
Fluorescent protein expression driven by her4 regulatory elements reveals the spatiotemporal pattern of Notch signaling in the nervous system of zebrafish embryos.
2007,
Pubmed
Zhao,
Hedgehog regulates smoothened activity by inducing a conformational switch.
2007,
Pubmed
Zhou,
SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.
2000,
Pubmed
