The Varied Roles of Notch in Cancer

Aster, Jon C.; Pear, Warren S.; Blacklow, Stephen C.

doi:10.1146/annurev-pathol-052016-100127

Cited by 570 publications

(501 citation statements)

References 220 publications

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“…Physiologic Notch signaling, which is transduced by regulated intramembrane proteolysis (RIP), normally relies on ADAM10 proteolysis at a juxtamembrane site (called S2), followed by γ-secretase cleavage at the inner membrane leaflet at site S3 to release its intracellular domain as a transcriptional effector (Aster et al, 2017; Bray, 2016; Kovall et al, 2017). Other important ADAM10 substrates identified from tissue specific knockouts, cell-based studies, and proteomic analyses include N-cadherin, pro-epidermal growth factor, betacellulin, HER2, NrCAM and ephrin receptors (Hartmann et al, 2002; Janes et al, 2005; Kuhn et al, 2016; Overall and Blobel, 2007; Reiss et al, 2005; Sahin et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10

Seegar

Killingsworth

Saha

et al. 2017

Cell

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128

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SUMMARY Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer’s precursor protein, APP. We present here the X-ray crystal structure of the ADAM10 ectodomain, which together with biochemical and cellular studies reveals how access to the enzyme active site is regulated. The enzyme adopts an unanticipated architecture, in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation.

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Section: Introductionmentioning

confidence: 99%

Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10

Seegar

Killingsworth

Saha

et al. 2017

Cell

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128

135

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“…Notch signaling controls development and tissue homeostasis in metazoan animals (reviewed in (Bray, 2016) and when dysregulated contributes to the pathogenesis of several hematologic malignancies and solid tumors (reviewed in (Aster et al, 2016)). Signaling relies on ligand-mediated proteolysis of Notch receptors by gamma-secretase, which releases the Notch intracellular domain (NICD), allowing it to translocate to the nucleus and form a Notch transcription complex (NTC) with the DNA-binding factor RBPJ and co-activators of the Mastermind-like (MAML) family.…”

Section: Introductionmentioning

confidence: 99%

A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas

et al. 2017

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Summary Gain-of-function Notch mutations are recurrent in mature small B-cell lymphomas such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), but the Notch target genes that contribute to B-cell oncogenesis are largely unknown. We performed integrative analysis of Notch-regulated transcripts, genomic binding of Notch transcription complexes, and genome conformation data to identify direct Notch target genes in MCL cell lines. This unique B-cell Notch regulome is largely controlled through Notch-bound distal enhancers and includes genes involved in B-cell receptor and cytokine signaling and the oncogene MYC, which sustains proliferation of Notch-dependent MCL cell lines via a Notch-regulated lineage-restricted enhancer complex. Expression of direct Notch target genes is associated with Notch activity in an MCL xenograft model and in CLL lymph node biopsies. Our findings provide key insights into the role of Notch in MCL and other B-cell malignancies and have important implications for therapeutic targeting of Notch-dependent oncogenic pathways.

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“…CBF1 serves as a DNA adaptor molecule that recruits either repressors or activators to transcriptional control elements like enhancers and transcription start sites of genes and is described as the major downstream effector of the cellular Notch signal transduction pathway [1]. Notch signaling controls the development and differentiation of diverse organs and tissues.…”

Section: Introductionmentioning

confidence: 99%

EBF1 binds to EBNA2 and promotes the assembly of EBNA2 chromatin complexes in B cells

et al. 2017

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Epstein-Barr virus (EBV) infection converts resting human B cells into permanently proliferating lymphoblastoid cell lines (LCLs). The Epstein-Barr virus nuclear antigen 2 (EBNA2) plays a key role in this process. It preferentially binds to B cell enhancers and establishes a specific viral and cellular gene expression program in LCLs. The cellular DNA binding factor CBF1/CSL serves as a sequence specific chromatin anchor for EBNA2. The ubiquitous expression of this highly conserved protein raises the question whether additional cellular factors might determine EBNA2 chromatin binding selectively in B cells. Here we used CBF1 deficient B cells to identify cellular genes up or downregulated by EBNA2 as well as CBF1 independent EBNA2 chromatin binding sites. Apparently, CBF1 independent EBNA2 target genes and chromatin binding sites can be identified but are less frequent than CBF1 dependent EBNA2 functions. CBF1 independent EBNA2 binding sites are highly enriched for EBF1 binding motifs. We show that EBNA2 binds to EBF1 via its N-terminal domain. CBF1 proficient and deficient B cells require EBF1 to bind to CBF1 independent binding sites. Our results identify EBF1 as a co-factor of EBNA2 which conveys B cell specificity to EBNA2.

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The Varied Roles of Notch in Cancer

Cited by 570 publications

References 220 publications

Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10

Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10

A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas

EBF1 binds to EBNA2 and promotes the assembly of EBNA2 chromatin complexes in B cells

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