Abstract
Disabled-2 (DAB2) is a clathrin and cargo binding endocytic adaptor protein recognized for its multifaceted roles in signaling pathways involved in cellular differentiation, proliferation, migration, tumor suppression, and other fundamental homeostatic cellular mechanisms. The requirement for DAB2 in the canonical TGFβ signaling in fibroblasts suggested that a similar mechanism may exist in immune cells and that DAB2 may contribute to immunological tolerance and suppression of inflammatory responses. In this review, we synthesize the current state of knowledge on the roles of DAB2 in the cells of the innate and adaptive immune system, with particular focus on antigen presenting cells (APCs; macrophages and dendritic cells) and regulatory T cells (Tregs). The emerging role of DAB2 in the immune system is that of an immunoregulatory molecule with significant roles in Treg-mediated immunosuppression, and suppression of TLR signaling in APC. DAB2 itself is downregulated by inflammatory stimuli, an event that likely contributes to the immunogenic function of APC. However, contrary findings have been described in neuroinflammatory disorders, thus suggesting a highly context-specific roles for DAB2 in immune cell regulation. There is need for better understanding of DAB2 regulation and its roles in different immune cells, their specialized sub-populations, and their responses under specific inflammatory conditions.
Highlights
Disabled homolog 2 (DAB2) received its name due to a high degree of similarity to the aminoterminal of the Disabled (Dab) protein initially described in Drosophila melanogaster as involved in embryonic neural development
The molecular mechanisms by which DAB2 restricts the inflammatory profile in macrophages have been addressed by studies that demonstrated a pivotal role of DAB2 in inhibiting myeloid differentiation factor 88 (MyD88)- or TIR-domaincontaining adapter protein-inducing interferon-B (TRIF)dependent signaling after TLR activation [27, 34]
Colitis induced by the adoptive transfer of naïve CD4+CD45RBhigh T cells into Rag2−/− mice correlated with a reduction in DAB2 levels in CD11b+ dendritic cells (DCs) in the colonic lamina propria upon, suggesting that DAB2 plays a role in keeping the tolerogenic profile in intestinal DCs during homeostasis, and its downregulation may contribute to exacerbated immune responses in inflammatory bowel diseases (IBDs)
Summary
Disabled homolog 2 (DAB2) received its name due to a high degree of similarity to the aminoterminal of the Disabled (Dab) protein initially described in Drosophila melanogaster as involved in embryonic neural development. Promotes protective function of Tregs in experimental model of colitis [30] Overexpression mediates the promotion of a myeloproliferative syndrome in ICSBP KO mice [31] Protects from liver inflammation in LDLR−/− fed with HFD [32] Protects liver and lung from inflammation in murine model of endotoxemia [27] Dampens inflammatory cytokines in adipose tissue and protects from insulin-resistance in HFD mice [27] Aggravates MS severity in murine model of EAE [24] Mediates the anti-inflammatory effect of BRP on macrophages [33] Dab2+ myeloid cells in the brain correlates with inflammation induced by cryoinjury [35] Regulates inflammation in patients with active VKH [36] Inhibits efficacy of vaccine therapy against tumor [37]
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