The <scp>FBXW7‐NOTCH interactome</scp>: A ubiquitin proteasomal system‐induced crosstalk modulating oncogenic transformation in human tissues

Kar, Rohan; Jha, Saurabh; Ojha, Shreesh; Sharma, Ankur; Dholpuria, Sunny; Raju, Venkata Sita Rama; Prasher, Parteek; Chellappan, Dinesh Kumar; Gupta, Gaurav; Singh, Sachin Kumar; Paudel, Keshav Raj; Hansbro, Philip M.; Singh, Sandeep; Ruokolainen, Janne; Kesari, Kavindra Kumar; Dua, Kamal; Jha, Niraj Kumar

doi:10.1002/cnr2.1369

Cited by 16 publications

(14 citation statements)

References 106 publications

(132 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FBXW7, in particular, regulates NOTCH protein activity by controlling its half-life, maintaining optimum protein levels in the tissue. It is perhaps the most widely studied F-box protein due to its role in a panel of both normal and malignant cellular processes [ 187 , 188 ]; in fact, mutations of the FBXW7 gene have been identified in more than 30% of pediatric T-ALL [ 188 , 189 ] and several other hematological and non-hematological diseases [ 190 , 191 , 192 , 193 , 194 ] These mutations disrupt the direct interaction between FBXW7 and NICD and extend the half-life of NICD, thus mimicking the effects of canonical NOTCH1 mutations ( Figure 4 B). For example, T-ALL cells harboring FBXW7 mutations are generally resistant to GSI [ 180 , 188 ].…”

Section: Other Mechanisms Of Notch1 Activation In Cllmentioning

confidence: 99%

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

Pozzo

Bittolo

Tissino

et al. 2022

Cancers

View full text Add to dashboard Cite

The Notch signaling pathway plays a fundamental role for the terminal differentiation of multiple cell types, including B and T lymphocytes. The Notch receptors are transmembrane proteins that, upon ligand engagement, undergo multiple processing steps that ultimately release their intracytoplasmic portion. The activated protein ultimately operates as a nuclear transcriptional co-factor, whose stability is finely regulated. The Notch pathway has gained growing attention in chronic lymphocytic leukemia (CLL) because of the high rate of somatic mutations of the NOTCH1 gene. In CLL, NOTCH1 mutations represent a validated prognostic marker and a potential predictive marker for anti-CD20-based therapies, as pathological alterations of the Notch pathway can provide significant growth and survival advantage to neoplastic clone. However, beside NOTCH1 mutation, other events have been demonstrated to perturb the Notch pathway, namely somatic mutations of upstream, or even apparently unrelated, proteins such as FBXW7, MED12, SPEN, SF3B1, as well as physiological signals from other pathways such as the B-cell receptor. Here we review these mechanisms of activation of the NOTCH1 pathway in the context of CLL; the resulting picture highlights how multiple different mechanisms, that might occur under specific genomic, phenotypic and microenvironmental contexts, ultimately result in the same search for proliferative and survival advantages (through activation of MYC), as well as immune escape and therapy evasion (from anti-CD20 biological therapies). Understanding the preferential strategies through which CLL cells hijack NOTCH1 signaling may present important clues for designing targeted treatment strategies for the management of CLL.

show abstract

Section: Other Mechanisms Of Notch1 Activation In Cllmentioning

confidence: 99%

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

Pozzo

Bittolo

Tissino

et al. 2022

Cancers

View full text Add to dashboard Cite

show abstract

“…GSIs are wellknown pan-Notch inhibitors that show serious adverse effects in clinical trials, such as gastrointestinal toxicity. 79 In addition, formation of the NICD-CSL-MAML complex and ubiquitination of Notch receptors are both key processes of Notch signaling, 2,[80][81][82] and blocking these aspects may not only affect Notch4, but also Notch1-3 signaling pathways. Thus, the efficiency and safety of these treatment methods should be further evaluated in future studies.…”

Section: Blocking Notch4 Signal Transductionmentioning

confidence: 99%

Targeting Notch4 in Cancer: Molecular Mechanisms and Therapeutic Perspectives

Xiu¹,

Zeng²,

Shan³

et al. 2021

CMAR

View full text Add to dashboard Cite

The dysregulation of Notch signaling is found in many cancers and is closely related to cancer progression. As an important Notch receptor, abnormal Notch4 expression affects several tumor-cell behaviors, including stemness, the epithelial-mesenchymal transition, radio/chemoresistance and angiogenesis. In order to inhibit the oncogenic effects of Notch4 activation, several methods for targeting Notch4 signaling have been proposed. In this review, we summarize the known molecular mechanisms through which Notch4 affects cancer progression. Finally, we discuss potential Notch4-targeting therapeutic strategies as a reference for future research.

show abstract

“…The SCF complex ubiquitinates proteins and triggers proteasome degradation of intracellular proteins, including the NICDs of NOTCH1-4 themselves. FBXW7 mutations ( Figure 5 ), therefore, stabilize and promote the transcriptional activities of the NICD, and directly contribute to increased Notch pathway activity [ 123 ]—resulting in a net gain of Notch activity. This is further validated by observations that mutations or low expression levels of FBXW7 correlate with poor patient outcome and survival [ 4 , 124 ].…”

Section: Targeting Oncogenic Pathways In Hnsccmentioning

confidence: 99%

Shooting at Moving and Hidden Targets—Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas

Kałafut

Czerwonka

Anameriç

et al. 2021

Cancers

View full text Add to dashboard Cite

Head and Neck Squamous Cell Carcinoma (HNSCC) is often aggressive, with poor response to current therapies in approximately 40–50% of the patients. Current therapies are restricted to operation and irradiation, often combined with a small number of standard-of-care chemotherapeutic drugs, preferentially for advanced tumour patients. Only very recently, newer targeted therapies have entered the clinics, including Cetuximab, which targets the EGF receptor (EGFR), and several immune checkpoint inhibitors targeting the immune receptor PD-1 and its ligand PD-L1. HNSCC tumour tissues are characterized by a high degree of intra-tumour heterogeneity (ITH), and non-genetic alterations that may affect both non-transformed cells, such as cancer-associated fibroblasts (CAFs), and transformed carcinoma cells. This very high degree of heterogeneity likely contributes to acquired drug resistance, tumour dormancy, relapse, and distant or lymph node metastasis. ITH, in turn, is likely promoted by pronounced tumour cell plasticity, which manifests in highly dynamic and reversible phenomena such as of partial or hybrid forms of epithelial-to-mesenchymal transition (EMT), and enhanced tumour stemness. Stemness and tumour cell plasticity are strongly promoted by Notch signalling, which remains poorly understood especially in HNSCC. Here, we aim to elucidate how Notch signal may act both as a tumour suppressor and proto-oncogenic, probably during different stages of tumour cell initiation and progression. Notch signalling also interacts with numerous other signalling pathways, that may also have a decisive impact on tumour cell plasticity, acquired radio/chemoresistance, and metastatic progression of HNSCC. We outline the current stage of research related to Notch signalling, and how this pathway may be intricately interconnected with other, druggable targets and signalling mechanisms in HNSCC.

show abstract

The FBXW7‐NOTCH interactome: A ubiquitin proteasomal system‐induced crosstalk modulating oncogenic transformation in human tissues

Cited by 16 publications

References 106 publications

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

Targeting Notch4 in Cancer: Molecular Mechanisms and Therapeutic Perspectives

Shooting at Moving and Hidden Targets—Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas

Contact Info

Product

Resources

About