The Notch3 Receptor and Its Intracellular Signaling-Dependent Oncogenic Mechanisms

Bellavia, Diana; Checquolo, Saula; Palermo, Rocco; Screpanti, Isabella

doi:10.1007/978-3-319-89512-3_10

Diana Bellavia⁸,
Saula Checquolo⁹,
Rocco Palermo¹⁰ &
…
Isabella Screpanti⁸

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1066))

3604 Accesses
8 Citations

Abstract

During evolution, gene duplication of the Notch receptor suggests a progressive functional diversification. The Notch3 receptor displays a number of structural differences with respect to Notch1 and Notch2, most of which have been reported in the transmembrane and in the intracellular regions, mainly localized in the negative regulatory region (NRR) and trans-activation domain (TAD). Targeted deletion of Notch3 does not result in embryonic lethality, which is in line with its highly restricted tissue expression pattern. Importantly, deregulated Notch3 expression and/or activation, often results in disrupted cell differentiation and/or pathological development, most notably in oncogenesis in different cell contexts. Mechanistically this is due to Notch3-related genetic alterations or epigenetic or posttranslational control mechanisms. In this chapter we discuss the possible relationships between the structural differences and the pathological role of Notch3 in the control of mouse and human cancers. In future, targeting the unique features of Notch3-oncogenic mechanisms could be exploited to develop anticancer therapeutics.

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Abbreviations

ADAM:: A Disintegrin And Metalloprotease
DSL:: Delta, Serrate
ECD:: Extracellular domain
HD:: Heterodimerization domain
NICD:: Notch intracellular domain
NRR:: Negative regulatory region
TAD:: Trans-activation domain
LAG-2:: Notch Ligands or DSL ligands
T-ALL:: T-cell acute lymphoblastic leukemia
Ptcra:: Invariant preTα chain of the pre-T cell receptor
Tregs:: T regulatory cells
IKK:: Inhibitor of KAPPA-B kinase complex
PTM:: Post-translational modification
IK:: Ikaros
IK-DN:: Ikaros dominant negative isoforms
HUD:: RNA-binding protein D of the ELAV/Hu family
BORIS/CTCFL:: Brother Of Regulator of Imprinted Sites/CTCF-like protein
TCR:: T-cell receptor
NF-κB:: Nuclear factor-κB
N1ICD:: Notch1 intracellular domain
N2ICD:: Notch2 intracellular domain
N3ICD:: Notch3 intracellular domain.

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Acknowledgments

We thank members of Screpanti’s laboratory, whose comments and work have contributed to the realization of this chapter. Work in the author’s laboratories is supported by Grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC), Institut Pasteur - Fondazione Cenci-Bolognetti and Sapienza University of Rome. This chapter is dedicated to the memory of Professor Alberto Gulino.

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Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
Diana Bellavia & Isabella Screpanti
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
Saula Checquolo
Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy
Rocco Palermo

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Diana Bellavia
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Saula Checquolo
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Rocco Palermo
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Isabella Screpanti
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Correspondence to Isabella Screpanti .

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Institute of Biochemistry, University of Giessen, Giessen, Germany
Tilman Borggrefe
Institute of Biochemistry, University of Giessen, Giessen, Germany
Benedetto Daniele Giaimo

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Bellavia, D., Checquolo, S., Palermo, R., Screpanti, I. (2018). The Notch3 Receptor and Its Intracellular Signaling-Dependent Oncogenic Mechanisms. In: Borggrefe, T., Giaimo, B. (eds) Molecular Mechanisms of Notch Signaling. Advances in Experimental Medicine and Biology, vol 1066. Springer, Cham. https://doi.org/10.1007/978-3-319-89512-3_10

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DOI: https://doi.org/10.1007/978-3-319-89512-3_10
Published: 19 July 2018
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