Abstract
NOTCH proteins constitute a receptor family with a widely conserved role in cell cycle, growing and development regulation. NOTCH1, the best characterised member of this family, regulates the expression of key genes in cell growth and angiogenesis, playing an essential role in cancer development. These observations provide a relevant rationale to propose the inhibition of the intracellular domain of NOTCH1 (Notch1-IC) as a strategy for treating various types of cancer. Notch1-IC stability is mainly controlled by post-translational modifications. FBXW7 ubiquitin E3 ligase-mediated degradation is considered one of the most relevant, being the previous phosphorylation at Thr-2512 residue required. In the present study, we describe for the first time a new regulation mechanism of the NOTCH1 signalling pathway mediated by DYRK2. We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism. We show that DYRK2 regulation by chemotherapeutic agents has a relevant effect on the viability, motility and invasion capacity of cancer cells expressing NOTCH1. In summary, we reveal a novel mechanism of regulation for NOTCH1 which might help us to better understand its role in cancer biology.
Highlights
NOTCH proteins (NOTCH1-4) constitute a receptor family with a widely conserved role in cell cycle, growing, development regulation and cell fate determination [1]
Expression of Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) resulted in a dose-dependent decrease in Notch1-IC protein levels, which was accompanied by the appearance of slower migrating bands (Fig. 1a)
We describe DYRK2 as a new kinase that regulates NOTCH1 pathway via phosphorylation, controlling its protein levels and activity in response to DNA damage
Summary
NOTCH proteins (NOTCH1-4) constitute a receptor family with a widely conserved role in cell cycle, growing, development regulation and cell fate determination [1]. Once Notch1-IC enters the nucleus, and together with the DNA-binding protein CSL (CBF1—Suppressor of Hairless—LAG1) and the co-activator MAML1 (Mastermind-like transcriptional co-activator 1), it stimulates the transcription of target genes related to processes Such as proliferation, angiogenesis, cell survival and migration [5, 6]. Functional studies implicate Notch signalling in essentially all of the hallmarks of cancer, being associated with abnormal expression, high mutation rate and poor survival in several cancers such as lung, breast, gastric or lymphoid cancer [7,8,9,10,11] This oncogenic function of NOTCH in human cancers is related with its capacity to increase cell growth, centered on the ability to induce the expression of Myc [12, 13] and to enhance PI3K-Akt signalling [14]. These observations have provided a rationale for pharmacologic inhibition of Notch1-IC as a potential strategy for treating various cancers [17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
