Routing dynamics of the colony-stimulating factor 3 receptor and implications for intracellular signaling

Hematopoiesis is the tightly regulated formation of all blood cell types from hematopoietic stem cells, which in adults takes place in the bone marrow. The bone marrow of an average healthy adult produces approximately 10(11)-10(12) peripheral blood cells a day. This process largely depends on hematopoietic growth factors. The granulocyte colony-stimulating factor (CSF)-3 is a member of the cytokine class I superfamily of growth factors that plays an important role in granulopoiesis by stimulating proliferation, survival and differentiation of myeloid progenitor cells. CSF3 deficient mice develop severe neutropenia. Neutrophils are the most abundant white blood cells in man and are rapidly elevated in case of a bacterial infection. CSF3 is administered to neutropenia patients in order to increase peripheral neutrophil levels, thereby reducing the risk of bacterial infection. CSF3 is also commonly used for the mobilization of hematopoietic stem cells into peripheral blood, to facilitate their harvest for the purpose of transplantation. The biological activities of CSF3 are mediated by its binding to the granulocyte colony-stimulating factor receptor (CSF3R), which results in the activation of multiple intracellular signaling pathways such as the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Experiments reported in this thesis have specifically dealt with the mechanisms that regulate intracellular trafficking of the CSF3R and the implications on signaling. There are several negative regulatory pathways responsible for switching-off CSF3R signaling. CSF3R internalization and lysosomal routing is one of the major negative feedback mechanisms described and involves SOCS3 dependent ubiquitination of CSF3R juxtamembrane lysine (K)632

p62 Is Required for Stem Cell/Progenitor Retention through Inhibition of IKK/NF-kB/Ccl4 Signaling at the Bone Marrow Macrophage-Osteoblast Niche

In the bone marrow (BM), hematopoietic progenitors (HPs) reside in specific anatomical niches near osteoblasts (Obs), macrophages (MFs), and other cells forming the BM microenvironment. A connection between immunosurveillance and traffic of HP has been demonstrated, but the regulatory signals that instruct the immune regulation of HP circulation are unknown. We discovered that the BM microenvironment deficiency of p62, an autophagy regulator and signal organizer, results in loss of autophagic repression of macrophage contact-dependent activation of Ob NF-kB signaling. Consequently, Ob p62-deficient mice lose bone, Ob Ccl4 expression, and HP chemotaxis toward Cxcl12, resulting in egress of short-term hematopoietic stem cells and myeloid progenitors. Finally, Ccl4 expression and myeloid progenitor egress are reversed by deficiency of the p62 PB1- binding partner Nbr1. A functional ‘‘MF-Ob niche’’ is required for myeloid progenitor/short-term stem cell retention, in which Ob p62 is required to maintain NF-kB signaling repression, osteogenesis, and BM progenitor retention

Заболевание тазобедренного сустава у детей с наследственной предрасположенностью: концептуальная модель

На основе принципов интегративной медицины, системного подхода с использованием концептуально−логического моделирования разработана единая система представлений о заболеваниях тазобедренного сустава у детей с наследственной предрасположенностью. Показано, что предлагаемый интегративный подход может служить основой для разработки диагностических и прогностических критериев развития суставов и проведения патогенетического хирургического лечения, направленного на ликвидацию или существенное снижение частоты формирования диспластического коксартроза.Based on the principles of integrative medicine, systemic approach with the use of concept of logical modelling, a uniform system of concepts about the diseases of the hip joint in children with hereditary susceptibility was worked out. It was shown that the suggested integrative approach can be used for working out diagnostic and prognostic criteria of joint development and performing pathogenetic surgery aimed at elimination or reduction in the frequency of forming dysplastic coxarthrosis

The miR-17/92 cluster: a comprehensive update on its genomics, genetics, functions and increasingly important and numerous roles in health and disease.

The miR-17/92 cluster is among the best-studied microRNA clusters. Interest in the cluster and its members has been increasing steadily and the number of publications has grown exponentially since its discovery with more than 1000 articles published in 2012 alone. Originally found to be involved in tumorigenesis, research work in recent years has uncovered unexpected roles for its members in a wide variety of settings that include normal development, immune diseases, cardiovascular diseases, neurodegenerative diseases and aging. In light of its ever-increasing importance and ever-widening regulatory roles, we review here the latest body of knowledge on the cluster\u27s involvement in health and disease as well as provide a novel perspective on the full spectrum of protein-coding and non-coding transcripts that are likely regulated by its members

The deubiquitinating enzyme DUB2A enhances CSF3 signalling by attenuating lysosomal routing of the CSF3 receptor

International audienceUbiquitination of the colony-stimulating factor 3 receptor (CSF3R) occurs after activated CSF3Rs are internalized and reside in early endosomes. CSF3R ubiquitination is crucial for lysosomal routing and degradation. The E3 ligase suppressor of cytokine signalling 3 (SOCS3) has been shown to play a major role in this process. Deubiquitinating enzymes remove ubiquitin moieties from target proteins by proteolytic cleavage. Two of these enzymes, AMSH and UBPY, interact with the general endosomal sorting machinery. Whether deubiquitinating enzymes control CSF3R trafficking from early towards late endosomes is unknown. In the present study, we asked whether AMSH, UBPY or a murine family of deubiquitinating enzymes could fulfil such a role. This DUB family comprises four members (DUB1, DUB1A, DUB2, and DUB2A), which were originally described as being hematopoietic-specific and cytokine inducible, but their function in cytokine receptor routing and signalling has remained largely unknown. Here, we show that DUB2A expression is induced by CSF3 in myeloid 32D cells and that DUB2 decreases ubiquitination and lysosomal degradation of the CSF3R, leading to prolonged signalling. These data support a model in which CSF3R receptor ubiquitination is dynamically controlled at the early endosome by feedback mechanisms involving CSF3-induced E3 ligase (SOCS3) and deubiquitinase (DUB2A) activities