DAB2IP

DAB2IP is a Ras (MIM 190020) GTPase-activating protein (GAP) that acts as a tumor suppressor. The DAB2IP gene is inactivated by methylation in prostate and breast cancers (Yano et al., 2005 [PubMed 15386433]).[supplied by OMIM, May 2010]

DAB2 Interacting Protein

Functions as a scaffold protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Involved in several processes such as innate immune response, inflammation and cell growth inhibition, apoptosis, cell survival, angiogenesis, cell migration and maturation. Plays also a role in cell cycle checkpoint control; reduces G1 phase cyclin levels resulting in G0/G1 cell cycle arrest. Mediates signal transduction by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF), interferon (IFN) or lipopolysaccharide (LPS). Modulates the balance between phosphatidylinositol 3-kinase (PI3K)-AKT-mediated cell survival and apoptosis stimulated kinase (MAP3K5)-JNK signaling pathways; sequesters both AKT1 and MAP3K5 and counterbalances the activity of each kinase by modulating their phosphorylation status in response to proinflammatory stimuli. Acts as a regulator of the endoplasmic reticulum (ER) unfolded protein response (UPR) pathway; specifically involved in transduction of the ER stress-response to the JNK cascade through ERN1. Mediates TNF-alpha-induced apoptosis activation by facilitating dissociation of inhibitor 14-3-3 from MAP3K5; recruits the PP2A phosphatase complex which dephosphorylates MAP3K5 on 'Ser-966', leading to the dissociation of 13-3-3 proteins and activation of the MAP3K5-JNK signaling pathway in endothelial cells. Mediates also TNF/TRAF2-induced MAP3K5-JNK activation, while it inhibits CHUK-NF-kappa-B signaling. Acts a negative regulator in the IFN-gamma-mediated JAK-STAT signaling cascade by inhibiting smooth muscle cell (VSMCs) proliferation and intimal expansion, and thus, prevents graft arteriosclerosis (GA). Acts as a GTPase-activating protein (GAP) for the ADP ribosylation factor 6 (ARF6) and Ras. Promotes hydrolysis of the ARF6-bound GTP and thus, negatively regulates phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent TLR4-TIRAP-MyD88 and NF-kappa-B signaling pathways in endothelial cells in response to lipopolysaccharides (LPS). Binds specifically to phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 3-phosphate (PtdIns3P). In response to vascular endothelial growth factor (VEGFA), acts as a negative regulator of the VEGFR2-PI3K-mediated angiogenic signaling pathway by inhibiting endothelial cell migration and tube formation. In the developing brain, promotes both the transition from the multipolar to the bipolar stage and the radial migration of cortical neurons from the ventricular zone toward the superficial layer of the neocortex in a glial-dependent locomotion process. Probable downstream effector of the Reelin signaling pathway; promotes Purkinje cell (PC) dendrites development and formation of cerebellar synapses. Functions also as a tumor suppressor protein in prostate cancer progression; prevents cell proliferation and epithelial-to-mesenchymal transition (EMT) through activation of the glycogen synthase kinase-3 beta (GSK3B)-induced beta-catenin and inhibition of PI3K-AKT and Ras-MAPK survival downstream signaling cascades, respectively.

Activation of JUN kinase activity Source: BHF-UCL
Activation of MAPKKK activity Source: UniProtKB
Angiogenesis Source: UniProtKB-KW
Cell cycle Source: UniProtKB-KW
Cell motility involved in cerebral cortex radial glia guided migration Source: UniProtKB
Cellular protein catabolic process Source: UniProtKB
Cellular response to epidermal growth factor stimulus Source: BHF-UCL
Cellular response to interleukin-1 Source: UniProtKB
Cellular response to lipopolysaccharide Source: UniProtKB
Cellular response to tumor necrosis factor Source: UniProtKB
Cellular response to unfolded protein Source: ParkinsonsUK-UCL
Cellular response to vascular endothelial growth factor stimulus Source: UniProtKB
Endothelial cell apoptotic process Source: BHF-UCL
Extrinsic apoptotic signaling pathway via death domain receptors Source: BHF-UCL
I-kappaB phosphorylation Source: UniProtKB
Inflammatory response Source: UniProtKB-KW
Innate immune response Source: UniProtKB-KW
Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress Source: BHF-UCL
Layer formation in cerebral cortex Source: UniProtKB
MAPK cascade Source: Reactome
Negative regulation of angiogenesis Source: UniProtKB
Negative regulation of canonical Wnt signaling pathway Source: BHF-UCL
Negative regulation of cell population proliferation Source: UniProtKB
Negative regulation of cellular protein catabolic process Source: UniProtKB
Negative regulation of endothelial cell migration Source: UniProtKB
Negative regulation of epidermal growth factor receptor signaling pathway Source: BHF-UCL
Negative regulation of epithelial cell migration Source: UniProtKB
Negative regulation of epithelial cell proliferation Source: BHF-UCL
Negative regulation of epithelial to mesenchymal transition Source: UniProtKB
Negative regulation of ERK1 and ERK2 cascade Source: UniProtKB
Negative regulation of fibroblast proliferation Source: BHF-UCL
Negative regulation of G0 to G1 transition Source: UniProtKB
Negative regulation of GTPase activity Source: BHF-UCL
Negative regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
Negative regulation of MAP kinase activity Source: BHF-UCL
Negative regulation of NF-kappaB transcription factor activity Source: BHF-UCL
Negative regulation of phosphatidylinositol 3-kinase activity Source: UniProtKB
Negative regulation of phosphatidylinositol 3-kinase signaling Source: UniProtKB
Negative regulation of protein phosphorylation Source: UniProtKB
Negative regulation of protein serine/threonine kinase activity Source: UniProtKB
Negative regulation of Ras protein signal transduction Source: BHF-UCL
Negative regulation of toll-like receptor 4 signaling pathway Source: UniProtKB
Negative regulation of transcription, DNA-templated Source: UniProtKB
Negative regulation of transcription by RNA polymerase II Source: BHF-UCL
Negative regulation of vascular endothelial growth factor receptor signaling pathway Source: UniProtKB
Negative regulation of vascular endothelial growth factor signaling pathway Source: UniProtKB
Neuron projection morphogenesis Source: UniProtKB
Positive regulation of apoptotic process Source: UniProtKB
Positive regulation of apoptotic signaling pathway Source: UniProtKB
Positive regulation of cell cycle arrest Source: UniProtKB
Positive regulation of dendrite development Source: UniProtKB
Positive regulation of GTPase activity Source: GOC
Positive regulation of IRE1-mediated unfolded protein response Source: ParkinsonsUK-UCL
Positive regulation of JNK cascade Source: UniProtKB
Positive regulation of JUN kinase activity Source: BHF-UCL
Positive regulation of MAPK cascade Source: UniProtKB
Positive regulation of neuron migration Source: UniProtKB
Positive regulation of neuron projection development Source: UniProtKB
Positive regulation of proteasomal protein catabolic process Source: UniProtKB
Positive regulation of protein catabolic process Source: UniProtKB
Positive regulation of protein-containing complex assembly Source: ParkinsonsUK-UCL
Positive regulation of protein serine/threonine kinase activity Source: UniProtKB
Positive regulation of synapse maturation Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Reelin-mediated signaling pathway Source: InterPro
Regulation of growth Source: UniProtKB-KW
Regulation of GTPase activity Source: UniProtKB
Regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
Regulation of p38MAPK cascade Source: UniProtKB
Regulation of protein-containing complex assembly Source: UniProtKB
Tube formation Source: UniProtKB
Vascular endothelial growth factor receptor-2 signaling pathway Source: UniProtKB

Cell membrane; Cytoplasm; Membrane; Dendrite. Localized in soma and dendrites of Purkinje cells as well as in scattered cell bodies in the molecular layer of the cerebellum (By similarity). Colocalizes with TIRAP at the plasma membrane. Colocalizes with ARF6 at the plasma membrane and endocytic vesicles. Translocates from the plasma membrane to the cytoplasm in response to TNF-alpha. Phosphatidylinositol 4-phosphate (PtdIns4P) binding is essential for plasma membrane localization.

A chromosomal aberration involving DAB2IP is found in a patient with acute myeloid leukemia (AML). Translocation t(9;11)(q34;q23) with KMT2A/MLL1. May give rise to a KMT2A/MLL1-DAB2IP fusion protein lacking the PH domain (PubMed:14978793).

In response to TNF-alpha-induction, phosphorylated at Ser-728; phosphorylation leads to a conformational change, and thus, increases its association with 14-3-3 proteins, MAP3K5, RIPK1 and TRAF2 in endothelial cells; also stimulates regulatory p85 subunit sequestring and PI3K-p85 complex activity inhibition.