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Adaptor proteins play central roles in the assembly of molecular complexes and coordinated activation of specific pathways. Through their modular domain structure, the NCK family of adaptor proteins (NCK1 and NCK2) link protein targets via their single SRC Homology (SH) 2 and three SH3 domains. Classically, their SH2 domain binds to phosphotyrosine motif-containing receptors (e.g. receptor tyrosine kinases), while their SH3 domains bind polyproline motif-containing cytoplasmic effectors. Due to these functions being established for both NCK1 and NCK2, their roles were inaccurately assumed to be redundant. However, in contrast with this previously held view, NCK1 and NCK2 now have a growing list of paralog-specific functions, which underscores the need to further explore their differences. Here we review current evidence detailing how these two paralogs are unique, including differences in their gene/protein regulation, binding partners and overall contributions to cellular functions. To help explain these contrasting characteristics, we then discuss SH2/SH3 structural features, disordered interdomain linker regions and post-translational modifications. Together, this review seeks to highlight the importance of distinguishing NCK1 and NCK2 in research and to pave the way for investigations into the origins of their interaction specificity. [ABSTRACT FROM AUTHOR]

Elevated basal serum tryptase levels are present in 4-6% of the general population, but the cause and relevance of such increases are unknown. Previously, we described subjects with dominantly inherited elevated basal serum tryptase levels associated with multisystem complaints including cutaneous flushing and pruritus, dysautonomia, functional gastrointestinal symptoms, chronic pain, and connective tissue abnormalities, including joint hypermobility. Here we report the identification of germline duplications and triplications in the TPSAB1 gene encoding α-tryptase that segregate with inherited increases in basal serum tryptase levels in 35 families presenting with associated multisystem complaints. Individuals harboring alleles encoding three copies of α-tryptase had higher basal serum levels of tryptase and were more symptomatic than those with alleles encoding two copies, suggesting a gene-dose effect. Further, we found in two additional cohorts (172 individuals) that elevated basal serum tryptase levels were exclusively associated with duplication of α-tryptase-encoding sequence in TPSAB1, and affected individuals reported symptom complexes seen in our initial familial cohort. Thus, our findings link duplications in TPSAB1 with irritable bowel syndrome, cutaneous complaints, connective tissue abnormalities, and dysautonomia.

Background Nephrin is a transmembrane protein with well-established signaling roles in kidney podocytes, and a smaller set of secretory functions in pancreatic β cells are implicated in diabetes. Nephrin signaling is mediated in part through its 3 cytoplasmic YDxV motifs, which can be tyrosine phosphorylated by high glucose and β cell injuries. Although in vitro studies demonstrate these phosphorylated motifs can regulate β cell vesicle trafficking and insulin release, in vivo evidence of their role in this cell type remains to be determined. Methods To further explore the role of nephrin YDxV phosphorylation in β cells, we used a mouse line with tyrosine to phenylalanine substitutions at each YDxV motif (nephrin-Y3F) to inhibit phosphorylation. We assessed islet function via primary islet glucose-stimulated insulin secretion assays and oral glucose tolerance tests. Results Nephrin-Y3F mice successfully developed pancreatic endocrine and exocrine tissues with minimal structural differences. Unexpectedly, male and female nephrin-Y3F mice showed elevated insulin secretion, with a stronger increase observed in male mice. At 8 months of age, no differences in glucose tolerance were observed between wild-type (WT) and nephrin-Y3F mice. However, aged nephrin-Y3F mice (16 months of age) demonstrated more rapid glucose clearance compared to WT controls. Conclusion Taken together, loss of nephrin YDxV phosphorylation does not alter baseline islet function. Instead, our data suggest a mechanism linking impaired nephrin YDxV phosphorylation to improved islet secretory ability with age. Targeting nephrin phosphorylation could provide novel therapeutic opportunities to improve β cell function. [ABSTRACT FROM AUTHOR]

In dry southwestern South Tyrol, Italy, rock glaciers are dominant landforms of the high-mountain cryosphere. Their spatial distribution and degree of activity hold critical information on the current state of discontinuous permafrost and consequently on the response potential to climate warming. Traditional geomorphologic mapping, however, owing to the qualitative expert-based nature, typically displays a high degree of uncertainty and variability among operators with respect to the dynamic classification of intact (permafrost-bearing) and relict (permafrost-devoid) rock glaciers. This limits the reliability of geomorphologic rock glacier inventories for basic and applied purposes. To address this limitation, (i) we conduct a systematic evaluation of the improvements that synthetic aperture radar interferometry (InSAR) can afford to the detection and dynamic classification of rock glaciers and (ii) build an integrated inventory that combines the strengths of geomorphologic- and InSAR-based approaches. To exploit fully InSAR-based information towards a better understanding of the topo-climatic conditions that sustain creeping permafrost, we further explore how velocity and the spatial distribution of moving areas (MAs) within rock glaciers may vary as a function of simple topographic variables known to exert first-order controls on incoming solar radiation, such as elevation and aspect. Starting from a geomorphologic inventory (n=789), we characterize the kinematics of InSAR-based MAs and the relevant hosting rock glaciers on 36 Sentinel-1 interferograms in the 2018–2019 period. With respect to the original inventory, InSAR analysis allowed us to identify 14 previously undetected rock glaciers. Further, it confirmed that 246 (76 %) landforms, originally interpreted as intact, do exhibit detectable movement (i.e., ≥1 cm yr -1) and that 270 (60 %) of the relict labeled counterparts do not, whereas 144 (18 %) were kinematically undefined due to decorrelation. Most importantly, InSAR proved critical for reclassifying 121 (15 %) rock glaciers, clarifying that 41 (13 %) of those interpreted as being intact do not exhibit detectable movement and that 80 (17 %) of the original relict ones do move. Reclassification (i) allowed us to identify a cluster of intact rock glaciers below 2000 m a.s.l. associated with positive mean annual air temperature (MAAT), and (ii) by increasing the altitudinal overlap between intact and relict rock glaciers, it depicts a broad transition belt in the aspect–elevation space, which varies from 50 m on west-facing slopes to 500 m on easterly ones. This finding deteriorates the significance of elevation and aspect as topographic proxies for modeling permafrost occurrence and highlights the importance of using InSAR to inform such models. From a process-oriented standpoint, InSAR information proves fundamental for imaging how this altitudinal transition manifests through changing rates and styles of rock glacier surface deformation. Specifically, we find that, as rock glaciers move faster, an increasingly larger proportion of their surface becomes kinematically involved (i.e., percent MA cover) and that this proportion increases with elevation up to 2600–2800 m, beyond which an inflection occurs and consistent average values are attained. Considering that the inflection falls between the -1 and -2 °C MAAT – the lower boundary for discontinuous permafrost – and is independent of slope gradient, we conclude that this altitudinal pattern represents a geomorphic signature: the dynamic expression of increasing permafrost distribution, from sporadic to discontinuous. [ABSTRACT FROM AUTHOR]

In dry southwestern South Tyrol, Italy, rock glaciers are dominant landforms of the high-mountain cryosphere. Their spatial distribution and degree of activity hold critical information on the past and current state of discontinuous permafrost, and consequently on response potential to climate warming. Traditional geomorphologic mapping, however, owing to the qualitative expert-based nature, typically displays a high degree of uncertainty and variability among operators with respect to the dynamic classification of intact (permafrost bearing) and relict (permafrost devoid) rock glaciers. This limits the reliability of geomorphologic rock glacier inventories for basic and applied purposes. To address this limitation: (i) we conduct a systematic evaluation of the improvements that InSAR-based information can afford to the detection and dynamic classification of rock glaciers; and (ii) build an integrated inventory that wishes to combine the strengths of geomorphologic- and InSAR-based approaches. To exploit fully InSAR-based information towards a better understanding of the topo-climatic conditions that sustain creeping permafrost, we further explore how velocity and the spatial distribution of moving areas (MAs) within rock glaciers may vary as a function of simple topographic variables known to exert first-order controls on incoming solar radiation, such as elevation and aspect. Starting from the compilation of a geomorphologic inventory (n = 789), we characterize the kinematics of InSAR-based MAs and the relevant hosting rock glaciers on thirty-six Sentinel-1 interferograms computed over 6-through 342-day baselines in the 2018-19 period. With respect to the original inventory, InSAR analysis allowed identifying 14 previously undetected rock glaciers. Further, it confirmed that 246 (76%) landforms, originally interpreted as intact, do exhibit detectable movement (i.e., =1 cm yr-1), and that 270 (60%) of the relict labelled counterparts do not, whereas 144 (18 %) resulted kinematically undefined due to decorrelation. Most importantly, InSAR proved critical for reclassifying 121 (15%) rock glaciers, clarifying that 41 (13%) of those interpreted as intact, do not exhibit detectable movement, and that 80 (17%) of the original relict ones do actually move. Reclassification, by increasing the altitudinal overlap between intact and relict rock glaciers depicts a broad transition belt in the aspect-elevation space, the amplitude of which varies from as little as 50 m on west facing slopes to a maximum of 500 m on easterly ones. This finding deteriorates the significance of elevation and aspect as topographic proxies for modelling permafrost occurrence, and highlights the importance of using InSAR for informing such models. From a process-oriented standpoint, InSAR information proves fundamental for imaging how this altitudinal transition manifests through changing rates and styles of rock glacier surface deformation. Specifically, we find that as rock glaciers move faster, an increasingly larger proportion of their surface becomes kinematically involved (i.e., percent MA cover), and that this proportion increases with elevation up to the 2600-2800 m, beyond which an inflection occurs and consistent average values are attained. Considering that the inflection falls between the -1°C and -2 °C MAAT - the lower boundary for discontinuous permafrost - and is independent of slope gradient, we conclude that this altitudinal pattern represents a geomorphic signature: the dynamic expression of increasing permafrost distribution (i.e., from sporadic to discontinuous), until optimal thermal conditions are reached. [ABSTRACT FROM AUTHOR]

In addition to the infectious consequences of immunodeficiency, patients with Wiskott-Aldrich syndrome (WAS) often suffer from poorly understood exaggerated immune responses that result in autoimmunity and elevated levels of serum IgE. Here, we have shown that WAS patients and mice deficient in WAS protein (WASP) frequently develop IgE-mediated reactions to common food allergens. WASP-deficient animals displayed an adjuvant-free IgE-sensitization to chow antigens that was most pronounced for wheat and soy and occurred under specific pathogen-free as well as germ-free housing conditions. Conditional deletion of Was in [FOXP3.sup.+] Tregs resulted in more severe Th2-type intestinal inflammation than that observed in mice with global WASP deficiency, indicating that allergic responses to food allergens are dependent upon loss of WASP expression in this immune compartment. While WASP-deficient Tregs efficiently contained Th1- and Th17-type effector differentiation in vivo, they failed to restrain Th2 effector responses that drive allergic intestinal inflammation. Loss of WASP was phenotypically associated with increased GATA3 expression in effector memory [FOXP3.sup.+] Tregs, but not in naive-like [FOXP3.sup.+] Tregs, an effect that occurred independently of increased IL-4 signaling. Our results reveal a Treg- specific role for WASP that is required for prevention of Th2 effector cell differentiation and allergic sensitization to dietary antigens., Introduction Type 2 immunity is involved in a variety of host-defense functions, ranging from protection against parasites and support of epithelial barrier integrity to regulation of wound healing and control [...]