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PubMed2004

The cell fate determinant numb interacts with EHD/Rme-1 family proteins and has a role in endocytic recycling.

The adaptor protein Numb is necessary for the cell fate specification of progenitor cells in the Drosophila nervous system. Numb is evolutionarily conserved and previous studies have provided evidence for a similar functional role during mammalian development. The Numb protein has multiple protein-protein interaction regions including a phosphotyrosine binding (PTB) domain and a carboxy-terminal domain that contains conserved interaction motifs including an EH (Eps15 Homology) domain binding motif and alpha-adaptin binding site. In this study we identify the EHD/Rme-1/Pincher family of endocytic proteins as Numb interacting partners in mammals and Drosophila. The EHD/Rme-1 proteins function in recycling of plasma membrane receptors internalized by both clathrin-mediated endocytosis and a clathrin-independent pathway regulated by ADP ribosylation factor 6 (Arf6). Here we report that Numb colocalizes with endogenous EHD4/Pincher and Arf6 and that Arf6 mutants alter Numb subcellular localization. In addition, we present evidence that Numb has a novel function in endosomal recycling and intracellular trafficking of receptors.

ADP-Ribosylation Factor 6↗
PubMed2001

The neural RNA-binding protein Musashi1 translationally regulates mammalian numb gene expression by interacting with its mRNA.

Musashi1 (Msi1) is an RNA-binding protein that is highly expressed in neural progenitor cells, including neural stem cells. In this study, the RNA-binding sequences for Msi1 were determined by in vitro selection using a pool of degenerate 50-mer sequences. All of the selected RNA species contained repeats of (G/A)U(n)AGU (n = 1 to 3) sequences which were essential for Msi1 binding. These consensus elements were identified in some neural mRNAs. One of these, mammalian numb (m-numb), which encodes a membrane-associated antagonist of Notch signaling, is a likely target of Msi1. Msi1 protein binds in vitro-transcribed m-numb RNA in its 3'-untranslated region (UTR) and binds endogenous m-numb mRNA in vivo, as shown by affinity precipitation followed by reverse transcription-PCR. Furthermore, adenovirus-induced Msi1 expression resulted in the down-regulation of endogenous m-Numb protein expression. Reporter assays using a chimeric mRNA that combined luciferase and the 3'-UTR of m-numb demonstrated that Msi1 decreased the reporter activity without altering the reporter mRNA level. Thus, our results suggested that Msi1 could regulate the expression of its target gene at the translational level. Furthermore, we found that Notch signaling activity was increased by Msi1 expression in connection with the posttranscriptional down-regulation of the m-numb gene.

3T3 Cells↗
PubMed1989

[Analysis of subjective symptoms of coldness and numbness in the upper and lower limbs among patients with vibration syndrome].

Coldness and numbness of the lower limbs in patients with vibration syndrome were studied in correlation with the frequency of attacks of vibration-induced white finger (VWF), coldness and numbness of the upper limbs, and awakening at night due to numbness of the arm. Subjects were 229 patients aged 50-69 years without disease other than vibration syndrome who had mainly operated chain saws. The present study showed that patients with more frequent VWF attacks had a higher prevalence and frequency of coldness in the fingers, awakening at night due to numbness of the arm, and coldness and numbness in the legs. Particularly patients having almost daily attacks of VWF had a high prevalence of these symptoms. Positive correlation was observed in prevalence and frequency between coldness of the fingers and that of the legs, and between coldness and numbness in the legs. The prevalence of VWF, numbness and coldness of the fingers, and coldness of the legs was higher the longer the total chain saw operating period. The present findings suggest that patients with severe circulatory disturbances in the upper limbs have severe circulatory disturbance in the lower limbs. Further studies on circulatory disturbances in the lower limbs are indicated, and their mechanism involved should be also pursued from the pathogenetic point of view.

Aged↗
PubMed2006

Asymmetric localization of Numb:EGFP in dividing neuroepithelial cells during neurulation in Danio rerio.

In the neural plate and tube of the zebrafish embryo, cells divide with their mitotic spindles oriented parallel to the plane of the neuroepithelium, whilst in the neural keel and rod, the spindle is oriented perpendicular to it. This change is achieved by a 90 degrees rotation of the mitotic spindle. We cloned zebrafish homologues of the gene for the Drosophila cell fate determinant Numb, and analyzed the localization of EGFP fusion proteins in vivo in dividing neuroepithelial cells during neurulation. Whereas Numb isoform 3 and the related protein Numblike are localized in the cytoplasm, Numb isoform 1 is localized to the cell membrane. Time-lapse analyses showed that Numb 1 is distributed uniformly around the cell cortex in dividing cells during plate and keel stages, but becomes localized at the basolateral membrane of some dividing cells during the transition from neural rod to tube. Using in vitro mutagenesis and Numb:EGFP deletion constructs, we showed that the first 196 amino acids of Numb are sufficient for this localization. Furthermore, we found that an 11-amino acid insertion in the PTB domain is essential for localization to the cortex, whereas amino acids 2-12 mediate the basolateral localization in the neural tube stage.

Amino Acid Sequence↗
PubMed2001

The Lnx family proteins function as molecular scaffolds for Numb family proteins.

Drosophila Numb functions as a cell fate determinant during neurogenesis. We isolated a novel mammalian protein, Lnx2, which interacts with mammalian Numb and Numblike. Lnx2 and the related Lnx1 are multimodular proteins that bind to Numb via their NPXY motifs. In addition, Lnx proteins form oligomers either via their PDZ domains binding to PDZ-binding consensus motifs located in their C-termini or by homophilic oligomerization of their RING fingers. Therefore, Lnx proteins may form large networks by homomeric binding. In situ hybridization analysis revealed complementary patterns of Lnx1 and Lnx2 expression in developing and adult brain, although in several structures they are present in the same cell populations. Moreover, their expression patterns overlap with those of the Numb proteins. Oligomerization of Lnx2 and Numb binding occurs simultaneously. Therefore, our findings suggest that Lnx proteins may serve as molecular scaffolds that localize unrelated, interacting proteins, such as Numb, to specific subcellular sites.

Amino Acid Sequence↗
PubMed2004

Are avoidance and numbing distinct PTSD symptom clusters?

We present the conceptual basis and empirical evidence for considering avoidance and numbing as distinct posttraumatic stress disorder (PTSD) symptom clusters. The majority of data from factor analytic studies supports the position that avoidance and numbing are distinct symptom clusters. As well, the available data suggest that (a) different treatment modalities have differential effects on reducing avoidance but not numbing, (b) patients with more severe pretreatment numbing have poorer treatment outcomes, (c) avoidance and numbing have different patterns of correlation with depression, and (d) they have different correlations with physiological indices of attention. We conclude that avoidance and numbing are distinct PTSD symptom clusters. This distinction has implications for revising current diagnostic criteria. The recognition of this distinction may lead to advances in understanding and treating PTSD.

Adaptation, Psychological↗
PubMed1994

Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells.

The four cells of an external sense organ in the Drosophila peripheral nervous system, the neuron, its sheath cell, and two "outer support cells" that form the hair and socket, are derived from a common precursor, the sensory organ precursor (SOP), after two rounds of division. We determined by immunocytochemistry that numb is a membrane-associated protein which localizes asymmetrically to one-half of the predivisional SOP cell. Upon division, numb segregates differentially to one daughter. Loss of numb function causes the descendants of the SOP to differentiate inappropriately, producing four outer support cells and no neuron or sheath. Ectopic expression of numb during the time of SOP division results in a transformation that is opposite to the null mutant transformation. Thus, numb functions to determine the fates of the secondary precursors; the differential distribution of numb as the SOP divides generates an asymmetric division in which the daughter cells acquire distinct identities.

Animals↗
PubMed2006

Zebrafish Numb homologue: phylogenetic evolution and involvement in regulation of left-right asymmetry.

Numb and its homologue, Numb-like (Numbl), play important roles in mammalian development, but their role in embryonic development of lower vertebrates remains unknown. We cloned a zebrafish numb homologue (znumb) by searching database. znumb shows approximately 60% identity with mammalian Numb orthologs. Interstingly, znumb lacks two specific sequence motifs unique to Numbl orthologs. However, chromosomal localization of znumb gene revealed colinearity with genes located around mouse and human Numbl genes. Furthermore, multi-species comparisons of conserved phosphotyrosine-binding (PTB) domain sequences in Numb and Numbl proteins suggest that znumb is more closely related to Numbl than Numb. znumb mRNA was expressed in a wide variety of zebrafish adult tissues. Overexpression of znumb in embryos resulted in an absence, or reversal, of the normal leftward shift of the developing heart tube. Furthermore, no or bi-lateral transcripts of lefty2 were observed in znumb-expressing embryos, suggesting that the Notch signaling was essential for left-right field formation and maintenance in zebrafish, and that znumb perturbed this process through down-regulation of endogenous Notch signaling.

Animals↗
PubMed1999

NUMB localizes in the basal cortex of mitotic avian neuroepithelial cells and modulates neuronal differentiation by binding to NOTCH-1.

The importance of lateral inhibition mediated by NOTCH signaling is well demonstrated to control neurogenesis both in invertebrates and vertebrates. We have identified the chicken homolog of Drosophila numb, which suppresses NOTCH signaling. We show that chicken NUMB (c-NUMB) protein is localized to the basal cortex of mitotic neuroepithelial cells, suggesting that c-NUMB regulates neurogenesis by the modification of NOTCH signaling through asymmetrical cell division. Consistent with this suggestion, we show (1) that c-NUMB interferes with the nuclear translocation of activated c-NOTCH-1 through direct binding to the PEST sequence in the cytoplasmic domain of c-NOTCH-1 and (2) that c-NUMB interferes with c-NOTCH-1-mediated inhibition of neuronal differentiation.

Amino Acid Sequence↗
PubMed2001

Numb suppresses the negative complementation at the Notch locus of Drosophila melanogaster, suggesting a putative mechanism for negative complementation.

The mutant form of the intracellular asymmetrically localized Numb membrane-bound protein of Drosophila melanogaster suppresses the negative complementation of certain Abruptex (Ax) mutations of the Notch (N) locus encoding a transmembrane receptor protein in which the Ax mutations are mutations in the epidermal growth factor (EGF)-like repeats of the extracellular domain of the receptor. One model for how Ax mutants affect N function is that they are refractory to an antagonistic signal generated by an excess of N ligands. Genetically numb (nb) is an antagonist of N. In the absence of nb, cells follow the same fate as they would in the presence of a gain-of-function N allele, such as Ax. Numb has been shown to interact with the cytoplasmic domain of Notch. It is therefore suggested that numb counteracts the effect of Abruptex on Notch ligand binding, i.e. that Numb is an antagonist to the activation of the Notch signal generated by Notch ligands. Numb might accomplish this by interfering with the proteolytic cleavage of the Notch intracellular domain at the cell membrane. Thus, it seems possible that the mechanism of negative complementation of certain Ax mutants is the failure of this cleavage. Other possible mechanisms for negative complementation are also discussed.

Animals↗
PubMed1995

Asymmetric segregation of Numb and Prospero during cell division.

A cell can divide asymmetrically by specifically segregating a determinant into one of its daughter cells. The Numb protein is a candidate for such a determinant in the asymmetric cell divisions of the developing Drosophila nervous system. Numb is a membrane-associated protein that localizes asymmetrically during cell division and segregates into one daughter cell, where it is required for the specification of the correct cell fate. Here we show that a nuclear protein, Prospero, translocates to the membrane at the beginning of cell division and colocalizes with Numb throughout mitosis, suggesting a common mechanism for asymmetric segregation. Numb and Prospero localization is coupled to mitosis and tightly correlated with the position of one of the two centrosomes. In contrast to centrosome positioning, however, Numb and Prospero localization is independent of microtubules. Cytochalasin D treatment suggests that the process is also independent of actin. We propose that there is an organizer of asymmetric cell division which provides positional information for both the orientation of the mitotic spindle and asymmetric localization of Numb and Prospero.

Actins↗
PubMed2006

Ligand-of-Numb protein X is an endocytic scaffold for junctional adhesion molecule 4.

Junctional adhesion molecule 4 (JAM4) is a cell adhesion molecule that interacts with a tight junction protein, membrane-associated guanylate kinase inverted 1 (MAGI-1). Our previous studies suggest that JAM4 is implicated in the regulation of paracellular permeability and the signalings of hepatocyte growth factor. In this study, we performed yeast two-hybrid screening to search for an unidentified JAM4-binding protein and obtained one isoform of Ligand-of-Numb protein X1 (LNX1), LNXp70, that is an interactor of Numb. Ligand-of-Numb protein X1 is expressed in kidney glomeruli and intestinal epithelial cells, where JAM4 is also detected. Immunoprecipitation from kidney lysates supports the in vivo interaction of proteins. Biochemical studies reveal that JAM4 directly binds the second PDZ domain of LNX1 through its carboxyl terminus. Junctional adhesion molecule 4, LNX1 and Numb form a tripartite complex in vitro and are partially colocalized in heterologous cells. Ligand-of-Numb protein X1 facilitates endocytosis of JAM4 and is involved in transforming growth factor beta -induced redistribution of JAM4 in mammary epithelial cells. Experiments using dominant-negative constructs and RNA interference insure that Numb is necessary for the LNX1-mediated endocytosis of JAM4. All these findings indicate that LNX1 provides an endocytic scaffold for JAM4 that is implicated in the reorganization of cell junctions.

Animals↗
PubMed2006

High levels of Notch signaling down-regulate Numb and Numblike.

Inhibition of Notch signaling by Numb is critical for many cell fate decisions. In this study, we demonstrate a more complex relationship between Notch and the two vertebrate Numb homologues Numb and Numblike. Although Numb and Numblike at low levels of Notch signaling negatively regulated Notch, high levels of Notch signaling conversely led to a reduction of Numb and Numblike protein levels in cultured cells and in the developing chick central nervous system. The Notch intracellular domain but not the canonical Notch downstream proteins Hes 1 and Hey 1 caused a reduction of Numb and Numblike. The Notch-mediated reduction of Numblike required the PEST domain in the Numblike protein and was blocked by the proteasome inhibitor MG132. Collectively, these observations reveal a reciprocal negative regulation between Notch and Numb/Numblike, which may be of relevance for stabilizing asymmetric cell fate switches and for tumor development.

Animals↗
PubMed2002

LNX functions as a RING type E3 ubiquitin ligase that targets the cell fate determinant Numb for ubiquitin-dependent degradation.

LNX is a RING finger and PDZ domain containing protein that interacts with the cell fate determinant Numb. To investigate the function of LNX, we tested its RING finger domain for ubiquitin ligase activity. The isolated RING finger domain was able to function as an E2-dependent, E3 ubiquitin ligase in vitro and mutation of a conserved cysteine residue within the RING domain abolished its activity, indicating that LNX is the first described PDZ domain-containing member of the E3 ubiquitin ligase family. We have identified Numb as a substrate of LNX E3 activity in vitro and in vivo. In addition to the RING finger, a region of LNX, including the Numb PTB domain-binding site and the first PDZ domain, is required for Numb ubiquitylation. Expression of wild-type but not mutant LNX causes proteasome-dependent degradation of Numb and can enhance Notch signalling. These results suggest that the levels of mammalian Numb protein and therefore, by extension, the processes of asymmetric cell division and cell fate determination may be regulated by ubiquitin-dependent proteolysis.

Animals↗
PubMed2004

Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization.

Mouse Numb homologs antagonize Notch1 signaling pathways through largely unknown mechanisms. Here we demonstrate that conditional mouse mutants with deletion of numb and numblike in developing sensory ganglia show a severe reduction in axonal arborization in afferent fibers, but no deficit in neurogenesis. Consistent with these results, expression of Cre recombinase in sensory neurons from numb conditional mutants results in reduced endocytosis, a significant increase in nuclear Notch1, and severe reductions in axon branch points and total axon length. Conversely, overexpression of Numb, but not mutant Numb lacking alpha-adaptin-interacting domain, leads to accumulation of Notch1 in markedly enlarged endocytic-lysosomal vesicles, reduced nuclear Notch1, and dramatic increases in axonal length and branch points. Taken together, our data provide evidence for previously unidentified functions of Numb and Numblike in sensory axon arborization by regulating Notch1 via the endocytic-lysosomal pathways.

Animals↗
PubMed2004

Five-year follow-up of a randomized trial to assess pain and numbness after laparoscopic or open repair of groin hernia.

BACKGROUND: Claims that laparoscopic groin hernia repair is followed by less persisting pain and numbness than open mesh repair were tested by follow-up within a multicentre randomized clinical trial. METHODS: Participants in the UK Medical Research Council Laparoscopic Groin Hernia Trial were followed up by means of self-completed postal questionnaires from 2 to 5 years after trial entry. The principal measures were pain (groin and testicular) and numbness (groin and thigh). RESULTS: Seven hundred and fifty (80.8 per cent) of the original 928 participants returned at least one questionnaire between 2 and 5 years; respondents were similar to the baseline randomized groups. Fewer respondents in the laparoscopic group had groin pain (absolute differences varied between 7.9 and 2.0 per cent, but were of marginal statistical significance); rates of testicular pain were similar in the two groups. Groin numbness was reported about half as commonly at all time points in the laparoscopic group (P < 0.001); there were no significant differences in thigh numbness. CONCLUSION: Laparoscopic surgery was associated with less long-term numbness and probably less pain in the groin.

Follow-Up Studies↗
PubMed2005

Prediction of numbing and effortful avoidance in female rape survivors with chronic PTSD.

The purpose of the present study was to investigate the relationships among numbing, arousal, intrusion, and avoidance in a sample of 272 female rape survivors. Multiple regression analyses were conducted to test a theoretical model, which posits that hyperarousal and numbing are functionally related mechanisms and intrusions and avoidance are functionally related. Results supported the hypothesis that arousal explained the majority of the variance in numbing beyond that explained by avoidance and intrusion. In addition, intrusive symptoms explained the majority of the variance in effortful avoidance beyond that explained by numbing and arousal. The findings suggest that numbing and effortful avoidance may be separate mechanisms associated with symptoms of arousal and intrusion, respectively.

Adolescent↗
PubMed2005

Characterization of human LNX, a novel ligand of Numb protein X that is downregulated in human gliomas.

Gliomas are major tumors of the central nervous system with a wide spectrum of different tumor types. Ligand of Numb protein X (LNX) is PDZ domain containing protein that interacts with cell fate determinant Numb. cDNA microarray analysis was used to determine the expression of 13,939 genes in a set of 18 gliomas. It showed that human LNX was downregulated in 100% of gliomas including low- and high-grade ones, which was confirmed by Northern blot. In situ hybridization analysis revealed that LNX was lowly expressed in cytoplasm of glioma cells. Thus, LNX might act as a diagnostic marker and a potential therapeutic target for glioma. Two-hybrid screen in yeast was used to identify human LNX interacting proteins important for LNX function. It showed that human LNX interacted with Ski interacting protein (SKIP) via PDZ domains. The co-immunoprecipitation results suggested that LNX interacted with SKIP in HEK293 cells. LNX could affect the subcellular localization of Numb, which indicated that LNX might function as a molecular anchor that localized Numb to the subcellular site of its interaction with Notch. The presence of multiple protein binding domains involved in signal transduction and interaction with Numb and SKIP suggested an important role for LNX in tumorogenesis.

Adaptor Proteins, Signal Transducing↗