Role Of Numb Research Articles

16-P029 Skeletal muscle cell fate decisions and the role of Numb

16-P029 Skeletal muscle cell fate decisions and the role of Numb

A role for Numb in p53 stabilization

Loss of Numb could enable breast cancer cells to bypass the p53 tumor suppressor response

Numb Cells Keep Moving

Integrins are heterodimeric transmembrane receptors that bind to components of the extracellular matrix and are important for both cellular adhesion and migration. Clustering of activated integrins on the substrate-facing surface of the leading edge of a cell results in the recruitment of various proteins, including actin stress fibers, to form a focal adhesion complex (FAC). Cells migrate, in part, through the coordinated assembly of focal adhesions at the leading edge of a cell and the disassembly of such complexes at the rear of the cell. Integrins are thought to move from the rear of the cell to the front through recycling endosomes, although the mechanisms that mediate internalization of integrins are not fully understood. Numb is a cargo-specific adaptor protein that binds to several endocytic proteins and is perhaps best known for its role in down-regulating the signaling of Notch, a transmembrane receptor that affects cellular proliferation and differentiation. Nishimura et al . previously demonstrated that Numb localizes to the tips of growing axons in cultures of hippocampal neurons and that it plays a role in the internalization of the adhesion molecule L1, so they investigated a role for Numb in mediating integrin endocytosis and cell migration. The authors used immunohistochemistry to demonstrate the colocalization of Numb with clathrin-coated structures in various endothelial and epithelial cell cultures. Analysis of green fluorescent protein (GFP) fusions of wild-type and mutant Numb proteins showed that the α-adaptin-binding motif was necessary for the interaction of Numb with clathrin-coated structures. In a monolayer wounding assay, Numb polarized toward the leading edge of migrating cells (just behind the lamellipodium). Numb localized around focal adhesions, and this association was inhibited by disruption of polymerized actin (F-actin). Immunostaining demonstrated the colocalization of Numb and β 1 -integrin at focal adhesions, and recombinant Numb protein coprecipitated β 1 - and β 3 -integrin but not other components of FACs. Depletion of Numb by siRNA reduced the number of β 1 -integrin-positive endosomes in migrating HeLa cells and also markedly reduced the number of HeLa cells that migrated toward integrin ligands compared with control siRNA-treated HeLa cells. Coimmunoprecipitation experiments revealed that Numb bound to the PAR (for partitioning defective) polarization complex, PAR-3. This complex localizes to the leading edge of polarized migrating cells. One component of this complex, atypical protein kinase C (aPKC) phosphorylated Numb in vitro and in HeLa cells and, as a consequence, Numb no longer bound to integrins. The authors propose a model in which Numb binds to free integrin molecules (rather than disrupting FACs) and recruits them to clathrin-coated structures to initiate integrin recycling, and that the localization and function of Numb are negatively regulated by aPKC. T. Nishimura, K. Kaibuchi, Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3. Dev. Cell 13 , 15-28 (2007). [PubMed]

Factor structure of PTSD symptoms among west and central African refugees

Although trauma is widespread in Africa, Africans are unrepresented in the literature on posttraumatic stress disorder (PTSD). The authors used confirmatory factor analysis of responses to the Harvard Trauma Questionnaire to model PTSD symptom structure in a sample of African refugees presenting at a U.S. torture treatment clinic. They tested four models that are proposed in the literature and one based on their clinical experience in which some symptoms of hyperarousal were integrated into intrusion. Their findings support a preference for a 4-factor aroused intrusion model. Discussion focuses on interpretation of models, the role of numbing and avoidance, and the limitations of Euro American symptoms in non-Euro American populations.

Event-related potential dysfunction in posttraumatic stress disorder: the role of numbing

The purpose of this study was to examine the relationship between disturbance in event-related potentials (ERPs) and symptom clusters in posttraumatic stress disorder (PTSD). ERPs were recorded in 17 unmedicated civilian PTSD patients and 17 age- and sex-matched controls during a conventional auditory oddball task. PTSD symptom clusters (re-experiencing, active avoidance, numbing, hyperarousal) were correlated with ERP measures. The PTSD group showed ERP disturbances to target stimuli (reduced P200 and P300 and increased N200 amplitude, increased N200 and P300 latency) and reduced P200 amplitude to common stimuli compared to the control group. A significant negative correlation was found between the intensity of numbing symptoms and parietal P300 amplitude. This study replicates findings of disturbed N200 and P300 components in PTSD, reflecting impairments in stimulus discrimination and attention. The finding that numbing was associated with reduced attention processing (P300) is consistent with models positing a relationship between disordered arousal and attention in PTSD.

Eyeing a new role for Numb

Eyeing a new role for Numb