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Src or HGF signalling regulates Numb binding to E-cadherin and the Par complex. (A) Co-IP of Numb with E-cadherin, aPKC, Par6 or Par3 in ts-src-MDCKI cells in the absence (40°C) or presence of Src (35°C), or in MDCKII cells without or with HGF treatment. (B) Tyrosine phosphorylation of E-cadherin, aPKC, Par6 or Par3 was examined with a specific anti-phospho-tyrosine antibody (4G10) under conditions specified in (A). E-cadhrin, aPKC, Par6 and Par3 (100 kDa, 150 kD and 180 kDa isoforms) were phosphorylated when Src was activated. In contrast, under HGF treatment, only Par6 and the 150 kD Par3 isoform were significantly phosphorylated while E-cadherin was weakly phosphorylated. (C) Co-IP of aPKC with Par6, Par3 and Numb, respectively, under conditions specified in (A). Both Src activation and HGF treatment promoted aPKC binding to Numb, but attenuated its interaction with Par3. (D) Co-IP of E-cadherin with p120-catenin and β-catenin, respectively, under conditions specified in (A). Tyrosine phosphorylation of E-cadherin enhanced its binding to p120-, but not to β-catenin. The corresponding quantification analysis of (A), (B), (C) and (D) are shown below each western blot panel. The error bars represent mean±s.d.
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Epithelial-mesenchymal transition (EMT), which can be caused by aberrant tyrosine kinase signalling, marks epithelial tumour progression and metastasis, yet the underlying molecular mechanism is not fully understood. Here, we report that Numb interacts with E-cadherin (E-cad) through its phosphotyrosine-binding domain (PTB) and thereby regulates th...
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... the MDCKII strain is used more widely in the literature, we felt it necessary to repeat the experiments done in ts-src-MDCKI cells in this strain. As shown in Figure 2A, Numb bound strongly to E-cad in ts-src-MDCKI cells cultured at 401C in the absence of Src, but the interaction was abolished at 351C when Src was expressed. Similarly, Numb was decoupled from E-cad after HGF treatment of MDCKII cells (Figure 2A). ...Context 2
... shown in Figure 2A, Numb bound strongly to E-cad in ts-src-MDCKI cells cultured at 401C in the absence of Src, but the interaction was abolished at 351C when Src was expressed. Similarly, Numb was decoupled from E-cad after HGF treatment of MDCKII cells (Figure 2A). As E-cad is tyrosine phosphory- lated on Src expression or HGF stimulation ( Figure 2B), it is likely that phosphorylation of one or more Tyr residue at the YYY triad in E-cad abrogated its binding to Numb. ...Context 3
... Numb was decoupled from E-cad after HGF treatment of MDCKII cells (Figure 2A). As E-cad is tyrosine phosphory- lated on Src expression or HGF stimulation ( Figure 2B), it is likely that phosphorylation of one or more Tyr residue at the YYY triad in E-cad abrogated its binding to Numb. ...Context 4
... basal con- ditions when Src was not activated, Numb bound strongly to all three isoforms of Par3 (but most strongly to the 150 kDa variant) and moderately to aPKC. Nevertheless, on Src expression or HGF treatment, the Numb-aPKC interaction was significantly augmented, whereas the Numb-Par3 inter- action markedly reduced (Figure 2A and C; Supplementary Figure S1C). Furthermore, compared with a constitutive interaction between aPKC and Par6 that appeared to be independent of Src activation ( Figure 2C), Par3 was disso- ciated from the aPKC-Par6 complex in response to Src activation ( Figure 2C; Supplementary Figure S1C). ...Context 5
... on Src expression or HGF treatment, the Numb-aPKC interaction was significantly augmented, whereas the Numb-Par3 inter- action markedly reduced (Figure 2A and C; Supplementary Figure S1C). Furthermore, compared with a constitutive interaction between aPKC and Par6 that appeared to be independent of Src activation ( Figure 2C), Par3 was disso- ciated from the aPKC-Par6 complex in response to Src activation ( Figure 2C; Supplementary Figure S1C). In Tyrosine phosphorylation of E-cadherin, aPKC, Par6 or Par3 was examined with a specific anti-phospho-tyrosine antibody (4G10) under conditions specified in (A). ...Context 6
... on Src expression or HGF treatment, the Numb-aPKC interaction was significantly augmented, whereas the Numb-Par3 inter- action markedly reduced (Figure 2A and C; Supplementary Figure S1C). Furthermore, compared with a constitutive interaction between aPKC and Par6 that appeared to be independent of Src activation ( Figure 2C), Par3 was disso- ciated from the aPKC-Par6 complex in response to Src activation ( Figure 2C; Supplementary Figure S1C). In Tyrosine phosphorylation of E-cadherin, aPKC, Par6 or Par3 was examined with a specific anti-phospho-tyrosine antibody (4G10) under conditions specified in (A). ...Context 7
... the Numb-Par3 interaction was strengthened by PP2 treatment, but diminished in cells over-expressing v-Src (Supplementary Figure S1C and E). As Par3, Par6 and aPKC were all tyrosine phosphorylated by Src ( Figure 2B), it is likely that phosphorylation played an important function in shifting their respective binding affinity and preference for one another and for Numb. We next examined the effect of Src activation on the integrity of the cadherin complex by western blotting. ...Context 8
... bound strongly to b-catenin but only weakly to p120-catenin under basal conditions. In contrast, the E-cad-p120 interac- tion was enhanced in both ts-src-transformed (351C) and HGF-treated cells, whereas the E-cad-b-catenin interaction was significantly attenuated in v-src-transformed but not in HGF-treated cells, suggesting that the activation of Src in the latter case was not as pronounced as in the former ( Figure 2D). In agreement with these results, v-Src over- expression markedly augmented E-cad binding to p120-cate- nin, yet reduced its interaction with b-catenin. ...Context 9
... suggests that a physical binding between Numb and E-cad is necessary for the proper lateral membrane localization of the latter. To interrogate whether Numb is necessary for the localization of E-cad, we generated a stable clone of MDCKII in which Numb expression was ablated by a specific shRNA (Supplementary Figure S2A and B). Confocal immunofluorescence microscopy revealed that endogenous E-cad localized to the lateral membrane of cell-cell junction as expected. ...Context 10
... Numb is an endocytic adaptor protein that can promote the endocytosis of a bound protein (Santolini et al, 2000;Dho et al, 2006;Nishimura and Kaibuchi, 2007). In this regard, it is interesting to note that the PTB domain of Numb binds to a YENPTY motif present in the cytoplasmic tail of APP and promotes the endocytosis of the latter (Roncarati et al, 2002). As E-cad binds to Numb through its PTB domain, the C-terminus of Numb is free to interact with an EH domain-containing endocytic protein and/or with AP2 (Santolini et al, 2000;Dho et al, 2006). ...Similar publications
Background
Morphogenesis requires developmental processes to occur both at the right time and in the right place. During neural tube formation in the zebrafish embryo, the generation of the apical specializations of the lumen must occur in the center of the neural rod after the neural cells have undergone convergence, invagination and interdigitati...
Citations
... We found that PTBP1 regulates the matrix stiffness-dependent splicing of the adapter protein Numb among other splicing targets, and that this is accompanied by a change in protein expression of the corresponding Numb isoforms. Numb plays important roles in cell fate decisions, regulation of endocytic trafficking and lysosomal degradation of membrane receptors including Notch1, E-cadherin and the anaplastic lymphoma kinase [48,49]. Numb not only undergoes alternative splicing of exon 9 but also exon 3, giving rise to four different isoforms in vertebrates. ...
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.
... ESRP1 also regulates NUMB splicing, which influences cell polarity and cell-cell adhesion; the alternative splicing due to the lack of ESRP1 expression is crucial for EMT progression and stem cell maintenance (49,(82)(83)(84). NUMB is involved in cell polarity by binding to the Par polarity complex, and cell-cell adhesion by binding to the cytoplasmic region of E-cadherin through its protein binding (PTB) domain (82,85). When the exon transcribing the PTB domain is spliced out, there is a loss of the interaction with E-cadherin, cell-cell adhesion, and progression through EMT. ...
Background
Epithelial–mesenchymal transition (EMT) is often linked with carcinogenesis. However, EMT is also important for embryo development and only reactivates in cancer. Connecting how EMT occurs during embryonic development and in cancer could help us further understand the root mechanisms of cancer diseases.
Content
There are key regulatory elements that contribute to EMT and the induction and maintenance of stem cell properties during embryogenesis, tissue regeneration, and carcinogenesis. Here, we explore the implications of EMT in the different stages of embryogenesis and tissue development. We especially highlight the necessity of EMT in the mesodermal formation and in neural crest cells. Through EMT, these cells gain epithelial–mesenchymal plasticity (EMP). With this transition, crucial morphological changes occur to progress through the metastatic cascade as well as tissue regeneration after an injury. Stem-like cells, including cancer stem cells, are generated from EMT and during this process upregulate factors necessary for stem cell maintenance. Hence, it is important to understand the key regulators allowing stem cell awakening in cancer, which increases plasticity and promotes treatment resistance, to develop strategies targeting this cell population and improve patient outcomes.
Summary
EMT involves multifaceted regulation to allow the fluidity needed to facilitate adaptation. This regulatory mechanism, plasticity, involves many cooperating transcription factors. Additionally, posttranslational modifications, such as splicing, activate the correct isoforms for either epithelial or mesenchymal specificity. Moreover, epigenetic regulation also occurs, such as acetylation and methylation. Downstream signaling ultimately results in the EMT which promotes tissue generation/regeneration and cancer progression.
... Similarly Protein numb homolog encoded by NUMB has been shown to regulate cell polarity and cell-cell adhesion important in EMT/MET by complexing with E-cadherin through an N-terminal phosphotyrosine-binding (PTB) domain. Importantly, loss of NUMB/Ecadherin interaction is induced in EMT leading to loss of cell-cell adhesion and increased cell migration.307 Inclusion of an epithelial specific exon within the PTB domain appears to be required to promote the NUMB/E-cadherin interaction and upregulation of the isoform containing the epithelial-specific exon was predicted in PPCD1 corneal endothelium by DEXSeq analysis ...
Fuchs endothelial corneal dystrophy (FECD) and posterior polymorphous corneal dystrophy (PPCD) are clinically distinct heritable conditions associated with corneal endothelial barrier dysfunction that ultimately result in loss of corneal clarity and subsequent visual impairment. FECD is a common age-related corneal dystrophy that, in up to 80% of patients, is associated with a trinucleotide repeat expansion (termed CTG18.1) within an intronic region of the transcription factor encoding gene TCF4. PPCD is a rare autosomal dominant corneal dystrophy attributed to mutations in three distinct transcription factor encoding genes, (OVOL2 [PPCD1], ZEB1 [PPCD3] and GRHL2 [PPCD4]) that are all established regulators of epithelial-mesenchymal transition (EMT), suggesting a shared mechanisms of dysregulation may underlie distinct genetic subtypes of this disease. In this thesis I present the use of established patient-derived corneal endothelial cell (CEC) culture techniques in combination with next generation sequencing (NGS) based technologies to probe the genetic aetiologies and transcriptomic signatures of dysregulation underlying these diseases. Specifically, a novel amplification-free approach was developed, utilised, and refined to enable the CTG18.1 repeat expansions to be interrogated at the nucleotide level within a FECD patient cohort. This approach revealed striking levels of repeat length instability and mosaicism are associated with CTG18.1 expansion, advancing our understating of FECD pathophysiology in addition to more broadly illustrating the power of this long-read non-amplification dependant sequencing methodology to study repetitive genomic regions. RNA-seq data was generated from PPCD patient- and control-derived CEC cultures to define mechanism of transcriptomic dysregulation underlying disease and advance our understanding of the pathophysiology of this genetically heterogenous disease. Bioinformatic interrogation of these data highlighted dysregulated expression of the PPCD-associated OVOL2/ZEB1/GRHL2 axis and EMT-associated genes, and ectopic expression of corneal progenitor epithelium cell-type markers within the PPCD1 and PPCD3 corneal endothelium. Furthermore, epithelial cell-type- specific gene isoforms were upregulated in PPCD1 and PPCD3 corneal endothelium including targets of the epithelial splicing regulator protein, ESRP1. Over-expression of ESRP1 was subsequently modelled in immortalised endothelial cell line (HCEC12). Consequently, an upregulation of ESRP1 target gene epithelial-cell-type specific isoforms and corneal progenitor epithelium markers was discovered, suggesting a major role of ESRP1 in PPCD pathogenicity. Finally, a refined cohort of genetically unresolved PPCD patients recruited at Moorfields Eye Hospital (MEH) and General University Hospital (GUH), Prague, was established to identify additional genetic causes of PPCD.
... NUMB encodes a cell fate determinant [1] and conserved adaptor protein [2,3] that regulates endocytic trafficking and lysosomal degradation of membrane receptors such as Notch1 [4], Integrinβ1 [5], and E-cadherin [6,7]. Numb also promotes proteasomal degradation of Gli1 [8] and the stabilization of p53 [9]. ...
The endocytic adaptor protein Numb acts as a tumor suppressor through downregulation of oncogenic pathways in multiple cancer types. The identification of splicing alterations giving rise to changes in Numb protein isoform expression indicate that Numb also has tumor promoting activity, though the underlying mechanisms are unknown. Here we report that NUMB exon 9 inclusion, which results in production of a protein isoform with an additional 49 amino acids, is a feature of multiple cancer types including all subtypes of breast cancer and correlates with worse progression-free survival. Specific deletion of exon 9-included Numb isoforms (Exon9in) from breast cancer cells reduced cell growth and prevents spontaneous lung metastasis in a mouse model. Quantitative proteome profiling showed that loss of Exon9in causes downregulation of membrane receptors and adhesion molecules, as well as proteins involved in extracellular matrix organization and the epithelial-mesenchymal transition (EMT) state. In addition, exon 9 deletion caused remodeling of the endocytic network, decreased ITGβ5 surface localization, cell spreading on vitronectin and downstream signaling to ERK and SRC. Together these observations suggest that Exon9in isoform expression disrupts the endocytic trafficking functions of Numb, resulting in increased surface expression of ITGβ5 as well as other plasma membrane proteins to promote cell adhesion, EMT, and tumor metastasis.
... NUMB encodes for a key determinant of cell fate that regulates the trafficking of surface proteins such as Notch, integrins and E-cadherin and can undergo alternative splicing (Nishimura and Kaibuchi, 2007;McGill et al., 2009;Teckchandani et al., 2009;Wang et al., 2009). Inclusion of NUMB exon 12 is frequently observed in different types of cancer, leading to a 48 amino acid extension of the proline-rich region (PRR) of the NUMB protein (Chen et al., 2009;Zhang et al., 2014;Lu et al., 2015;Rajendran et al., 2016). ...
RNA-seq analysis of alternative pre-mRNA splicing has facilitated an unprecedented understanding of transcriptome complexity in health and disease. However, despite the availability of countless bioinformatic pipelines for transcriptome-wide splicing analysis, the use of these tools is often limited to expert bioinformaticians. The need for high computational power, combined with computational outputs that are complicated to visualize and interpret present obstacles to the broader research community. Here we introduce DJExpress , an R package for differential expression analysis of transcriptomic features and expression-trait associations. To determine gene-level differential junction usage as well as associations between junction expression and molecular/clinical features, DJExpress uses raw splice junction counts as input data. Importantly, DJExpress runs on an average laptop computer and provides a set of interactive and intuitive visualization formats. In contrast to most existing pipelines, DJExpress can handle both annotated and de novo identified splice junctions, thereby allowing the quantification of novel splice events. Moreover, DJExpress offers a web-compatible graphical interface allowing the analysis of user-provided data as well as the visualization of splice events within our custom database of differential junction expression in cancer (DJEC DB). DJEC DB includes not only healthy and tumor tissue junction expression data from TCGA and GTEx repositories but also cancer cell line data from the DepMap project. The integration of DepMap functional genomics data sets allows association of junction expression with molecular features such as gene dependencies and drug response profiles. This facilitates identification of cancer cell models for specific splicing alterations that can then be used for functional characterization in the lab. Thus, DJExpress represents a powerful and user-friendly tool for exploration of alternative splicing alterations in RNA-seq data, including multi-level data integration of alternative splicing signatures in healthy tissue, tumors and cancer cell lines.
... Robinot et al. (2021) reported a disruption of the epithelial barrier integrity and an alteration of the ZO-1 distribution at the tight junctions (TJs) during infection with SARS-CoV-2. LNX2 acts as a molecular scaffold for Numb family proteins, essential players in the regulation of cell adhesion and polarity (Wang et al., 2009). PARD3 is an essential protein in asymmetric cell division and in polarized growth. ...
The C-terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein E contains a PBM (PDZ-binding motif) targeting PDZ (PSD-95/Dlg/ZO-1) domains, which is identical to the PBM of SARS-CoV. The latter is involved in the pathogenicity of the virus. Recently, we identified 10 human PDZ-containing proteins showing significant interactions with SARS-CoV-2 protein E PBM. We selected several of them involved in cellular junctions and cell polarity (TJP1, PARD3, MLLT4, and LNX2) and MPP5/PALS1 previously shown to interact with SARS-CoV E PBM. Targeting cellular junctions and polarity components is a common strategy by viruses to hijack cell machinery to their advantage. In this study, we showed that these host PDZ domains TJP1, PARD3, MLLT4, LNX2, and MPP5/PALS1 interact in a PBM-dependent manner in vitro and colocalize with the full-length E protein in cellulo , sequestrating the PDZ domains to the Golgi compartment. We solved three crystal structures of complexes between human LNX2, MLLT4, and MPP5 PDZs and SARS-CoV-2 E PBM highlighting its binding preferences for several cellular targets. Finally, we showed different affinities for the PDZ domains with the original SARS-CoV-2 C-terminal sequence containing the PBM and the one of the beta variant that contains a mutation close to the PBM. The acquired mutations in the E protein localized near the PBM might have important effects both on the structure and the ion-channel activity of the E protein and on the host machinery targeted by the variants during the infection.
... ; https://doi.org/10.1101/2021.12.04.471219 doi: bioRxiv preprint barrier integrity and an alteration of the ZO-1 distribution at tight junctions (TJs) during infection with 81 SARS-CoV-2 (Robinot et al., 2021). LNX2 acts as a molecular scaffold for Numb family proteins, 82 essential players in the regulation of cell adhesion and polarity (Wang et al., 2009). PARD3 is an 83 essential protein in asymmetric cell division and in polarized growth. ...
The C-terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein E contains a PBM (PDZ binding motif) targeting PDZ (PSD-95/Dlg/ZO-1) domains identical to the PBM of SARS-CoV. The latter is involved in the pathogenicity of the virus. Recently, we identified ten human PDZ-containing proteins showing significant interactions with SARS-CoV-2 protein E PBM. We selected several of them involved in cellular junctions and cell polarity (TJP1, PARD3, MLLT4, LNX2) and MPP5/Pals1 previously shown to interact with SARS-CoV E PBM. Targeting cellular junctions and polarity components is a common strategy by viruses to hijack cell machinery to their advantage. In this study, we showed that these host PDZ domains TJP1, PARD3, MLLT4, LNX2 and MPP5/PALS1 interact in a PBM-dependent manner in vitro and colocalize with the full-length E protein in cellulo, sequestrating the PDZ domains to the Golgi compartment. We solved three crystal structures of complexes between human LNX2, MLLT4 and MPP5 PDZs and SARS-CoV-2 E PBM highlighting its binding preferences for several cellular targets. Finally, we showed different affinities for the PDZ domains with the original SARS-CoV-2 C-terminal sequence containing the PBM and the one of the beta variant that contains a mutation close to the PBM. The acquired mutations in E protein localized near the PBM might have important effects both on the structure and the ion-channel activity of the E protein and on the host machinery targeted by the variants during the infection.
... Another interesting discovery is Numb within the LGN-mINSC-Par3 cluster which was found to retain in one daughter cell in asymmetrically dividing MaSCs (Tosoni et al., 2015). Although a link to the polarity complex has not been shown in the mammary gland, an interaction with the Par complex was identified in MDCK cells (Wang et al., 2009). Thus, a combination of Par3, mINSC and Numb may be possible. ...
Oriented cell divisions (OCDs) represent a fundamental mechanism for tissue morphogenesis, repair and differentiation where the mitotic spindle is oriented along a specific polarity axis. Early research identified the evolutionarily conserved Gαi/LGN/NuMA ternary complex that mediates orientation of the mitotic spindle by being restricted to specific cortical regions. The mechanisms that control the recruitment of these proteins to the cortex remain unfolding, particularly in epithelial systems such as the mammary gland. The mammary gland represents a unique organ that develops predominantly after birth where postnatal morphogenesis of the mammary gland drives dramatic tissue turnover and remodelling. Thus, differentiation and proliferation are constantly balanced to allow normal mammary gland development and homeostasis. How mammary epithelial cells regulate mitotic spindle orientation, hence OCDs, to accompany the rapid and constant tissue turnover is not well understood. This study aimed to identify novel factors that regulate the LGN-mediated spindle orientation machinery and determine how their dysregulation affects OCDs in mammary epithelial cells. By combining co-immunoprecipitation with mass spectrometry, the LGN interactome at the cell cortex of mitotic mammary epithelial cells was characterised and the membrane-associated protein Annexin A1 (ANXA1) was identified as a novel partner of LGN. Confocal and time-lapse microscopy demonstrated a critical role of ANXA1 in regulating the position and planar orientation of the mitotic spindle by instructing the accumulation and restriction of the LGN complex at the lateral cortex. Moreover, loss of ANXA1 leads to mitotic spindle misassembly and chromosome segregation defects, affecting the dynamics and progression of mitosis. Collectively the present study identified ANXA1 as a novel intrinsic cue of OCDs in mammary epithelial cells. Given increasing evidence of a link between OCD and tumorigenesis, this work is not only important for advancing our understanding of normal epithelial biology but also elucidating how imbalance of OCDs can contribute to the abnormal cell behaviour observed in cancer.
... It can be serine and tyrosine phosphorylated, suggesting activation mediated by phosphorylation typical of signaling molecules. Tyrosine phosphorylation has been observed to mobilize Numb from the plasma membrane to the cytoplasm [28,29]. It thus becomes a prime candidate for a potential role in organizing signaling machines that control differentiation. ...
Retinoic acid (RA) is a fundamental regulator of cell cycle and cell differentiation. Using a leukemic patient-derived in vitro model of a non-APL AML, we previously found that RA evokes activation of a macromolecular signaling complex, a signalosome, built of numerous MAPK-pathway-related signaling molecules; and this signaling enabled Retinoic-Acid-Response-Elements (RAREs) to regulate gene expression that results in cell differentiation/cell cycle arrest. Toward mechanistic insight into the nature of this novel signaling, we now find that the NUMB cell fate determinant protein is an apparent scaffold for the signalosome. Numb exists in the cell bound to an ensemble of signalosome molecules, including Raf, Lyn, Slp-76, and Vav. Addition of RA induces the expression of Fgr. Fgr binds NUMB, which is associated with (p-tyr)phosphorylation of NUMB and enhanced NUMB-binding and (p-tyr)phosphorylation of select signalosome components, thereby betraying signalosome activation. Signalosome activation is associated with cell differentiation along the myeloid lineage and G1/0 cell cycle arrest. If RA-induced Fgr expression is ablated by a CRISPR-KO; then the RA-induced (p-tyr) phosphorylation of NUMB and enhanced NUMB-binding and (p-tyr)phosphorylation of select signalosome components are lost. The cells now fail to undergo RA-induced differentiation or G1/0 arrest. In sum we find that NUMB acts as a scaffold for a signaling machine that functions to propel RA-induced differentiation and G1/0 arrest, and that Fgr binding to NUMB turns the function on. The Numb fate determinant protein thus appears to regulate the retinoic acid embryonic morphogen using the Fgr Src-Family-Kinase. These mechanistic insights suggest therapeutic targets for a hitherto incurable AML.
... The polar complex protein (PAR) participated in coordinating this events and also serves to establish tight junctions, which suture adjacent epithelial cells, functionally separating the apical-basal lateral surface and restricting liquid flow between the intercellular spaces. Moreover, NUMB participated in the regulation of tight-junction kinetics by affecting and interacting with the localization of PAR3 (50,77,78). In summary, NUMB suppress the Notch signaling pathway by inhibiting EMT. ...
Cancer stem cells (CSCs) are a subpopulation of cancer that can self-renew and differentiate into large tumor masses. Evidence accumulated to date shows that CSCs affect tumor proliferation, recurrence, and resistance to chemotherapy. Recent studies have shown that, like stem cells, CSCs maintain cells with self-renewal capacity by means of asymmetric division and promote cell proliferation by means of symmetric division. This cell division is regulated by fate determinants, such as the NUMB protein, which recently has also been confirmed as a tumor suppressor. Loss of NUMB expression leads to uncontrolled proliferation and amplification of the CSC pool, which promotes the Notch signaling pathway and reduces the expression of the p53 protein. NUMB genes are alternatively spliced to produce six functionally distinct isoforms. An interesting recent discovery is that the protein NUMB isoform produced by alternative splicing of NUMB plays an important role in promoting carcinogenesis. In this review, we summarize the known functions of NUMB and NUMB isoforms related to the proliferation and generation of CSCs.
