The Multitasker Protein: A Look at the Multiple Capabilities of NUMB

Ortega-Campos, Sara M.; García-Heredia, José Manuel

doi:10.3390/cells12020333

Cited by 6 publications

(12 citation statements)

References 212 publications

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“…The Numb gene consists of 10 exons, and PTBP1 regulates the alternative splicing of exon 9, which results in the inclusion of exon 9 and the presence of an extra 46 amino acids in the proline rich region of the protein (Fig. 4A) [37, 38]. To test if the PTBP1-dependent alternative splicing of exon 9 of Numb is controlled by mechanical cues, we cultivated MCF10A breast epithelial cells on stiff or soft collagen-coated polyacrylamide gels and quantified the degree of inclusion of exon 9 in the mRNA, by polymerase chain reaction.…”

Section: Resultsmentioning

confidence: 99%

“…Exon 9 encodes for an additional 49 amino acids in the proline rich region of Numb and gives rise to the two largest isoforms P71/P72. Exon 3 codes for an 11 amino acid insert into the PTB domain of Numb [37]. The splicing of Numb is regulated during development with the isoforms that include exon 9 expressed in stem and progenitor cells and the isoform skipping exon 9 preferentially expressed in differentiated cells [50, 51].…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of how the Numb +E9 isoform promotes stiffness-induced cell proliferation is currently unknown. However, because Numb regulates receptor trafficking [37], it is possible that it results in increased recycling of receptor tyrosine kinases that are important for proliferation, which would increase the signalling input for cell proliferation in cells subjected to a stiff environment. This is supported by the fact that the Numb +E9 isoform but not the ΔE9 isoform regulates the recycling of the receptor tyrosine kinase ALK [64].…”

Section: Discussionmentioning

confidence: 99%

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Mechanical control of the splicing factor PTBP1 regulates extracellular matrix stiffness-induced cell proliferation and mechanomemory

Tseng,

Sun,

Salem

et al. 2024

Preprint

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Cells sense and respond to mechanical cues from their environment. Mechanical cues are important for many biological processes, including embryonic development, ageing, cellular homeostasis, and diseases. Cells translate mechanical cues into cellular biochemical signals that govern cellular behaviour, like cell proliferation or migration, via a process called mechanotransduction. However, this process and the proteins involved remain incompletely understood. Here, we present an unbiased and large-scale approach to identify proteins involved in mechanotransduction. The screen revealed that the splicing factor PTBP1 is a novel mechanotransducer. We show that the nuclear localisation of PTBP1 depends on extracellular matrix stiffness, cell density, and the actomyosin-based contractility of the cell. Furthermore, we demonstrate that PTBP1 promotes the mechanosensitive splicing of the adapter protein Numb and that alternative splicing of Numb is crucial for matrix stiffness-induced cell proliferation and mechanomemory. Our results support the idea that changes in alternative splicing are an integral part of mechanotransduction and provide a mechanism by which matrix stiffness regulates cell proliferation and the formation of a mechanomemory in cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mechanical control of the splicing factor PTBP1 regulates extracellular matrix stiffness-induced cell proliferation and mechanomemory

Tseng,

Sun,

Salem

et al. 2024

Preprint

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“…NUMB is an important protein during development (Wu & Li, 2015). It plays a role in cell polarization and asymmetric division during embryonic development (Ortega‐Campos & García‐Heredia, 2023; Zilian et al., 2001). In mice, NUMB was implicated in the regulation of cardiac morphogenesis and cardiac progenitor cell differentiation (Zhao et al., 2014).…”

Section: Analyses Of the De Novo Gene Listmentioning

confidence: 99%

Naturally occurring genetic diseases caused by de novo variants in domestic animals

Azevedo,

Amaro,

Niza‐Ribeiro

et al. 2024

Animal Genetics

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With the advent of next‐generation sequencing, an increasing number of cases of de novo variants in domestic animals have been reported in scientific literature primarily associated with clinically severe phenotypes. The emergence of new variants at each generation is a crucial aspect in understanding the pathology of early‐onset diseases in animals and can provide valuable insights into similar diseases in humans. With the aim of collecting deleterious de novo variants in domestic animals, we searched the scientific literature and compiled reports on 42 de novo variants in 31 genes in domestic animals. No clear disease‐associated phenotype has been established in humans for three of these genes (NUMB, ANKRD28 and KCNG1). For the remaining 28 genes, a strong similarity between animal and human phenotypes was recognized from available information in OMIM and OMIA, revealing the importance of comparative studies and supporting the use of domestic animals as natural models for human diseases, in line with the One Health approach.

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“…In ammatory-induced damage to Numb may contribute to the accumulation of undifferentiated NSCs or neural progenitors. This accumulation hinders the replenishment of mature and functional neurons [211,212]. Numb is crucial for balancing NSC proliferation and differentiation.…”

Section: Role Of Neuroin Ammation In Fueling Neurodegenerationmentioning

confidence: 99%

Investigating How Inflammation Involving NF-κB Signaling Disrupts the Genetic Architecture of Neurons/Neural Stem Cells and Fuels Neurodegeneration

Shafi,

Rajpar,

Yaqoob

et al. 2024

Preprint

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Background: Understanding how inflammation disrupts neural stem cells and neuronal genetic architecture is crucial. This investigation explores these mechanisms, aiming to decipher the role of inflammation in disrupting neuronal genetic architecture. Unraveling these complexities may reveal therapeutic targets, offering hope for precision interventions to impede or slow the progression of debilitating neurodegenerative conditions.Methods: Databases including PubMed, MEDLINE and Google Scholar were searched for published articles without any date restrictions, involving NF-κB and neurogenic genes/signaling pathways/transcription factors. They were investigated in the study to unravel how inflammation disrupts the neural stem cells (NSCs) and neuronal genetic architecture, and how this process fuels the development of neurodegeneration. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).Results: This study reveals how NF-κB activation plays a central role in inflammation-induced disruption, mediating transcriptional dysregulation of key neurogenic factors like Ngn1, NeuroD, and PDGF, compromising the neurogenic code. Downregulation of neurotrophic factors, notably BDNF, increases neuronal vulnerability to apoptotic pathways, accelerating neurodegeneration. Inflammatory processes extend to the genomic landscape, affecting genes crucial for neurogenesis and synaptic function, contributing to observed synaptic dysfunction in neurodegenerative diseases. Furthermore, inflammation disrupts NSCs, impairing neurogenesis and compromising neural progenitor dynamics, diminishing the regenerative potential of the nervous system. Identified therapeutic strategies include precision targeting of NF-κB, restoration of neurotrophic support, and interventions promoting proper gene expression and neurogenesis, offering promising avenues for mitigating inflammation-induced damage and halting neurodegenerative progression.Conclusion: This study investigates the intricate impact of inflammation on neural stem cells (NSCs) and neuronal genetic architecture, providing insights into the pathogenesis disrupting neuronal architecture. NF-κB-mediated disruptions compromise neurotrophic support, impair neurogenesis, induce synaptic dysfunction, and enhance vulnerability to apoptosis. This orchestrated genomic dysregulation contributes to the progression of neurodegenerative diseases. Therapeutically, precision targeting of NF-κB, restoration of neurotrophic support, and promotion of neurogenesis emerge as promising strategies to mitigate inflammation-induced damage, offering potential avenues for interventions to impede the neurodegenerative cascade.

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The Multitasker Protein: A Look at the Multiple Capabilities of NUMB

Cited by 6 publications

References 212 publications

Mechanical control of the splicing factor PTBP1 regulates extracellular matrix stiffness-induced cell proliferation and mechanomemory

Mechanical control of the splicing factor PTBP1 regulates extracellular matrix stiffness-induced cell proliferation and mechanomemory

Naturally occurring genetic diseases caused by de novo variants in domestic animals

Investigating How Inflammation Involving NF-κB Signaling Disrupts the Genetic Architecture of Neurons/Neural Stem Cells and Fuels Neurodegeneration

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