Disabled‐2: A modular scaffold protein with multifaceted functions in signaling

Abstract

Disabled-2 (Dab2) is a multimodular scaffold protein with signaling roles in the domains of cell growth, trafficking, differentiation, and homeostasis. Emerging evidences place Dab2 as a novel modulator of cell-cell interaction; however, its mode of action has remained largely elusive. In this review, we highlight the relevance of Dab2 function in cell signaling and development and provide the most recent and comprehensive analysis of Dab2's action as a mediator of homotypical and heterotypical interactions. Accordingly, Dab-2 controls the extent of platelet aggregation through various motifs within its N-terminus. Dab2 interacts with the cytosolic tail of the integrin receptor blocking inside-out signaling, whereas extracellular Dab2 competes with fibrinogen for integrin α IIb β 3 receptor binding and, thus, modulates outside-in signaling. An additional level of regulation results from Dab2's association with cell surface lipids, an event that defines the extent of cell-cell interactions. As a multifaceted regulator, Dab2 acts as a mediator of endocytosis through its association with the [FY]xNPx[YF] motifs of internalized cell surface receptors, phosphoinositides, and clathrin. Other emerging roles of Dab2 include its participation in developmental mechanisms required for tissue formation and in modulation of immune responses. This review highlights the various novel mechanisms by which Dab2 mediates an array of signaling events with vast physiological consequences.

Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations

“…In line with this, Dab2 was reported to influence a range of intracellular signaling cascades ranging from the Ras/MAPK pathway to TGFβ and Wnt signaling [255,257,258]. In addition, Dab2 was discovered to play roles in platelet physiology and immunology [259].…”

“…The strongest link between Dab2 and human disease is its loss in many cancers such as ovarian, breast, colon, prostate, esophageal, nasopharyngeal and head and neck cancer [256] which is likely due to abnormal promoter hypermethylation [259]. In fact, a short mRNA fragment of Dab2 was initially identified due to its selective absence from ovarian cancer cell lines and was accordingly coined "differentially expressed in ovarian cancer" (DOC-2) [263].…”

Involvement of DHH and GLI1 in adrenocortical autograft regeneration in rats

“…Absence of ZG in adrenocortical autograft was also previously reported 32 . DAB2 has multifaceted roles and is expressed in epithelial cells of several tissues 33 . DAB2 is also induced by physiological stimulations 34 .…”

Phosphorylation of Dab2 is involved in inhibited VEGF‐VEGFR‐2 signaling induced by downregulation of syndecan‐1 in glomerular endothelial cell

“…And it is reported to be involved in a number of pathophysiological changes through its roles in cellular trafficking of membrane receptor and signaling transduction (Tao et al, ). Researches have shown that Dab2 is capable of regulating transforming growth factor‐β (TGF‐β) signaling transduction by modulating internalization of TGF‐β receptor (Hocevar et al, ; Penheiter et al, ; Finkielstein and Capelluto, ). Dab2 is extensively studied in tumor biology (Moore et al, ; Liu et al ).…”