Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex

Ishitani, Tohru; Hirao, Tomoko; Suzuki, Maho; Isoda, Miho; Ishitani, Shizuka; Harigaya, Kenichi; Kitagawa, Motoo; Matsumoto, Kunihiro; Itoh, Motoyuki

doi:10.1038/ncb2028

Cited by 115 publications

(101 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RET encodes a receptor tyrosine kinase that is implicated in the development of endocrine tumors (38). As MAP4K2, NLK is also a mitogen-activated protein kinase (MAPK)-like kinase and suppresses Notch signaling (34). The Notch and MAPK signaling have crucial functions in determining cell fates and in regulation of cell growth, differentiation, and stress responses.…”

Section: Discussionmentioning

confidence: 99%

Mammary gland morphological and gene expression changes underlying pregnancy protection of breast cancer tumorigenesis

Misra¹,

Bentley²,

Bond³

et al. 2012

Physiological Genomics

View full text Add to dashboard Cite

A full-term pregnancy early in life reduces lifetime risk of developing breast cancer, and the effect can be mimicked in rodents by full-term pregnancy or shortterm treatment with exogenous estrogen and progesterone. To gain insight into the protective mechanism, 15 3-mo-old postpubertal virgin Lewis rats were randomly assigned to three groups: control (C), pregnancy (P), or hormone (H). The P group animals underwent a full-term pregnancy, and H group animals were implanted subcutaneously with silastic capsules filled with ethynyl estradiol and megesterol acetate for 21 days. C and P animals were implanted with sham capsules. On day 21 capsules were removed, which was followed by a 49-day involution period, euthanasia, and mammary tissue collection. Global gene expression was measured using Rat Genome 230.2 Arrays. Histological analysis revealed that P and H treatments induced sustained morphological changes in the mammary gland with significantly increased percentages of mammary parenchyma and stromal tissues and higher ratio of stroma to parenchyma. Transcriptome analysis showed that P and H treatments induced sustained global changes in gene expression in the mammary gland. Analysis of commonly up-and downregulated genes in P and H relative to C treatment showed increased expression of three matrix metallopeptidases (Mmp3, 8, and 12), more differentiated mammary phenotype, enhanced innate and adaptive immunity, and reduced cell proliferation and angiogenic signatures. The sustained morphological and global gene expression changes in mammary tissue after pregnancy and hormone treatment may function together to provide the protective effect against breast cancer. breast cancer protection; hormone; pregnancy BREAST CANCER IS ONE OF THE most common cancers in women and affects nearly 10% of all women in US. In the year 2009, 192,370 new cases of invasive and 62,280 new cases of in situ breast cancer were estimated to have occurred, with 40,170 estimated deaths (3). Various epidemiological studies have revealed that multiple factors including hormones, genetics, reproductive history, radiation, socio-economic status, place of residence, ethnicity, and the environment affect the incidence of breast cancer (9,19,28,29,50,51,60). It has been shown that full-term pregnancy early in life has a protective effect on women against the risk of breast cancer irrespective of genetic background, age, race, or ethnic background (2,37,39,40,64,65,72). For instance, Lambe et al. (1996) (39, 40) and Albrektsen et al. (2005) (2) reported that full-term gestation in a woman younger than 24 yr of age reduces her lifetime risk of developing breast cancer, and this parity-induced protection against breast cancer is significantly affected by the total number of pregnancies. The epidemiological data on breastfeeding and breast cancer risk in humans also show that prolonged breast-feeding confers additional protection against breast cancer (17). However, aborted pregnancies are not associated with decreased risk for breast cancer (8).A ...

show abstract

Section: Discussionmentioning

confidence: 99%

Mammary gland morphological and gene expression changes underlying pregnancy protection of breast cancer tumorigenesis

Misra¹,

Bentley²,

Bond³

et al. 2012

Physiological Genomics

View full text Add to dashboard Cite

show abstract

“…However, as the degree of reduction of the activation evoked by the four NotchICs in the MamL1-deficient fibroblasts is variable (20-50% of the wild-type cells, depending on the type of NotchIC), subtle preferences between Mam and Notch species might exist. Recombinant Notch1IC and RBP-J proteins form complexes in vitro in the absence of Mam (Ishitani et al, 2010;Nam et al, 2003). In the Mam-NotchIC-RBP-J transcription-activating complex, a major activation domain is provided by Notch (Kurooka and Honjo, 2000;Oyama et al, 2007).…”

Section: ;Maml3mentioning

confidence: 99%

“…The formation of this complex is negatively regulated by phosphorylation of Notch by Nemo-like kinase, an evolutionarily conserved, multifunctional protein kinase (Ishitani et al, 2010). The multifunctional transcriptional repressor Bcl6 competes with Mam for association with Notch and CSL to repress selected target genes (Sakano et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Mastermind-like 1 (MamL1) and mastermind-like 3 (MamL3) are essential for Notch signaling in vivo

et al. 2011

Self Cite

View full text Add to dashboard Cite

SUMMARYMastermind (Mam) is one of the elements of Notch signaling, a system that plays a pivotal role in metazoan development. Mam proteins form transcriptionally activating complexes with the intracellular domains of Notch, which are generated in response to the ligand-receptor interaction, and CSL DNA-binding proteins. In mammals, three structurally divergent Mam isoforms (MamL1, MamL2 and MamL3) have been identified. There have also been indications that Mam interacts functionally with various other transcription factors, including the p53 tumor suppressor, -catenin and NF-B. We have demonstrated previously that disruption of MamL1 causes partial deficiency of Notch signaling in vivo. However, MamL1-deficient mice did not recapitulate total loss of Notch signaling, suggesting that other members could compensate for the loss or that Notch signaling could proceed in the absence of Mam in certain contexts. Here, we report the generation of lines of mice null for MamL3. Although MamL3-null mice showed no apparent abnormalities, mice null for both MamL1 and MamL3 died during the early organogenic period with classic pan-Notch defects. Furthermore, expression of the lunatic fringe gene, which is strictly controlled by Notch signaling in the posterior presomitic mesoderm, was undetectable in this tissue of the double-null embryos. Neither of the single-null embryos exhibited any of these phenotypes. These various roles of the three Mam proteins could be due to their differential physical characteristics and/or their spatiotemporal distributions. These results indicate that engagement of Mam is essential for Notch signaling, and that the three Mam isoforms have distinct roles in vivo.

show abstract

“…It has been recently reported that Notch can be phosphorylated on multiple sites by Nemo-like kinase (NLK), and the density of NLK phosphorylation sites in Notch serves as a molecular rheostat to fine-tune Notch activity. Knockdown of NLK leads to hyperactivation of Notch signalling, and consequently decreases neurogenesis in zebrafish (Ishitani et al, 2010). It would be interesting to know whether this mode of regulation in the Notch signaling pathway also exists in mammalian eyelid morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

Notch gain of function in mouse periocular mesenchyme downregulates FoxL2 and impairs eyelid levator muscle formation, leading to congenital blepharophimosis

Zhang

Kao

Pelosi

et al. 2011

Journal of Cell Science

View full text Add to dashboard Cite

SummaryNotch signaling is pivotal for the morphogenesis and homeostasis of many tissues. We found that aberrant Notch activation in mouse neural-crest-derived periocular mesenchymal cells (POMCs), which contribute to the formation of corneal and eyelid stroma, results in blepharophimosis. Compound transgenic mice overexpressing the Notch1 intracellular domain (N1-ICD) in POMCs (POMC N1-ICD ) showed relatively minor effects on the cornea, but increased cell apoptosis and decreased cell proliferation during eyelid morphogenesis. Eyelid closure at E15.5 and eyelid formation at birth were incomplete. In further analyses, overexpression of N1-ICD impaired eyelid levator smooth muscle formation by downregulating the transcription factor FoxL2. This is similar to the effect of haploinsufficiency of FOXL2 in humans, which results in type II BPES (blepharophimosis, ptosis and epicanthus inversus syndrome). In vitro studies showed that FoxL2 expression is augmented by a low dose of N1-ICD but was downregulated by a high dose, depending on the extent of Hes-1 and Hey-1 activation. Moreover, transfection of CMV-FoxL2 enhanced -SMA promoter activity. These data strongly imply that a physiologically low level of Notch1 is crucial for proper FoxL2 expression in POMCs, which is, in turn, essential for Müeller muscle formation and normal eyelid development.

show abstract

Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex

Cited by 115 publications

References 38 publications

Mammary gland morphological and gene expression changes underlying pregnancy protection of breast cancer tumorigenesis

Mammary gland morphological and gene expression changes underlying pregnancy protection of breast cancer tumorigenesis

Mastermind-like 1 (MamL1) and mastermind-like 3 (MamL3) are essential for Notch signaling in vivo

Notch gain of function in mouse periocular mesenchyme downregulates FoxL2 and impairs eyelid levator muscle formation, leading to congenital blepharophimosis

Contact Info

Product

Resources

About