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Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1.

ABSTRACT: Intramembrane proteolysis by presenilin-dependent gamma-secretase produces the Notch intracellular cytoplasmic domain (NCID) and Alzheimer disease-associated amyloid-beta. Here, we show that upon Notch signaling the intracellular domain of Notch-1 is cleaved into two distinct types of NICD species due to diversity in the site of S3 cleavage. Consistent with the N-end rule, the S3-V cleavage produces stable NICD with Val at the N terminus, whereas the S3-S/S3-L cleavage generates unstable NICD with Ser/Leu at the N terminus. Moreover, intracellular Notch signal transmission with unstable NICDs is much weaker than that with stable NICD. Importantly, the extent of endocytosis in target cells affects the relative production ratio of the two types of NICD, which changes in parallel with Notch signaling. Surprisingly, substantial amounts of unstable NICD species are generated from the Val-->Gly and the Lys-->Arg mutants, which have been reported to decrease S3 cleavage efficiency in cultured cells. Thus, we suggest that the existence of two distinct types of NICD points to a novel aspect of the intracellular signaling and that changes in the precision of S3 cleavage play an important role in the process of conversion from extracellular to intracellular Notch signaling.

SUBMITTER: Tagami S

PROVIDER: S-EPMC2223315 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1.

Tagami Shinji S Okochi Masayasu M Yanagida Kanta K Ikuta Akiko A Fukumori Akio A Matsumoto Naohiko N Ishizuka-Katsura Yoshiko Y Nakayama Taisuke T Itoh Naohiro N Jiang Jingwei J Nishitomi Kouhei K Kamino Kouzin K Morihara Takashi T Hashimoto Ryota R Tanaka Toshihisa T Kudo Takashi T Chiba Shigeru S Takeda Masatoshi M

Molecular and cellular biology 20071029 1

Intramembrane proteolysis by presenilin-dependent gamma-secretase produces the Notch intracellular cytoplasmic domain (NCID) and Alzheimer disease-associated amyloid-beta. Here, we show that upon Notch signaling the intracellular domain of Notch-1 is cleaved into two distinct types of NICD species due to diversity in the site of S3 cleavage. Consistent with the N-end rule, the S3-V cleavage produces stable NICD with Val at the N terminus, whereas the S3-S/S3-L cleavage generates unstable NICD wi ...[more]

PMID: 17967888

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Project description:NOTCH1, NOTCH2, NOTCH3 and NOTCH4 are transmembrane receptors that transduce juxtacrine signals of the delta‑like canonical Notch ligand (DLL)1, DLL3, DLL4, jagged canonical Notch ligand (JAG)1 and JAG2. Canonical Notch signaling activates the transcription of BMI1 proto‑oncogene polycomb ring finger, cyclin D1, CD44, cyclin dependent kinase inhibitor 1A, hes family bHLH transcription factor 1, hes related family bHLH transcription factor with YRPW motif 1, MYC, NOTCH3, RE1 silencing transcription factor and transcription factor 7 in a cellular context‑dependent manner, while non‑canonical Notch signaling activates NF‑κB and Rac family small GTPase 1. Notch signaling is aberrantly activated in breast cancer, non‑small‑cell lung cancer and hematological malignancies, such as T‑cell acute lymphoblastic leukemia and diffuse large B‑cell lymphoma. However, Notch signaling is inactivated in small‑cell lung cancer and squamous cell carcinomas. Loss‑of‑function NOTCH1 mutations are early events during esophageal tumorigenesis, whereas gain‑of‑function NOTCH1 mutations are late events during T‑cell leukemogenesis and B‑cell lymphomagenesis. Notch signaling cascades crosstalk with fibroblast growth factor and WNT signaling cascades in the tumor microenvironment to maintain cancer stem cells and remodel the tumor microenvironment. The Notch signaling network exerts oncogenic and tumor‑suppressive effects in a cancer stage‑ or (sub)type‑dependent manner. Small‑molecule γ‑secretase inhibitors (AL101, MRK‑560, nirogacestat and others) and antibody‑based biologics targeting Notch ligands or receptors [ABT‑165, AMG 119, rovalpituzumab tesirine (Rova‑T) and others] have been developed as investigational drugs. The DLL3‑targeting antibody‑drug conjugate (ADC) Rova‑T, and DLL3‑targeting chimeric antigen receptor‑modified T cells (CAR‑Ts), AMG 119, are promising anti‑cancer therapeutics, as are other ADCs or CAR‑Ts targeting tumor necrosis factor receptor superfamily member 17, CD19, CD22, CD30, CD79B, CD205, Claudin 18.2, fibroblast growth factor receptor (FGFR)2, FGFR3, receptor‑type tyrosine‑protein kinase FLT3, HER2, hepatocyte growth factor receptor, NECTIN4, inactive tyrosine‑protein kinase 7, inactive tyrosine‑protein kinase transmembrane receptor ROR1 and tumor‑associated calcium signal transducer 2. ADCs and CAR‑Ts could alter the therapeutic framework for refractory cancers, especially diffuse‑type gastric cancer, ovarian cancer and pancreatic cancer with peritoneal dissemination. Phase III clinical trials of Rova‑T for patients with small‑cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch‑related knowledge‑base and optimize Notch‑targeted therapy for patients with cancer.

Dataset Information

Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1.

Publications

Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1.

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