DAB2IP
Description
The DAB2IP (DAB2 interacting protein) is a protein-coding gene located on chromosome 9.
Disabled homolog 2-interacting protein is a protein that in humans is encoded by the DAB2IP gene. DAB2IP is a Ras (MIM 190020) GTPase-activating protein (GAP) that acts as a tumor suppressor gene and is inactivated by methylation in prostate and breast cancers (Yano et al., 2005).[supplied by OMIM] DAB2IP has been shown to interact with DAB2.
DAB2IP functions as a scaffold protein, playing a crucial role in regulating a wide array of signaling pathways, both general and specialized. It is involved in diverse cellular processes including innate immune response, inflammation, cell growth inhibition, apoptosis, cell survival, angiogenesis, cell migration, and maturation. DAB2IP also contributes to cell cycle checkpoint control, reducing G1 phase cyclin levels and leading to G0/G1 cell cycle arrest. It mediates signal transduction triggered by receptor-mediated inflammatory signals, such as tumor necrosis factor (TNF), interferon (IFN), or lipopolysaccharide (LPS). DAB2IP modulates the balance between phosphatidylinositol 3-kinase (PI3K)-AKT-mediated cell survival and apoptosis-stimulated kinase (MAP3K5)-JNK signaling pathways. It sequesters both AKT1 and MAP3K5, counterbalancing their activity by modulating their phosphorylation status in response to pro-inflammatory stimuli. DAB2IP acts as a regulator of the endoplasmic reticulum (ER) unfolded protein response (UPR) pathway, specifically involved in transducing the ER stress-response to the JNK cascade through ERN1. It mediates TNF-alpha-induced apoptosis activation by facilitating the dissociation of inhibitor 14-3-3 from MAP3K5, recruiting 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. DAB2IP also mediates TNF/TRAF2-induced MAP3K5-JNK activation while inhibiting CHUK-NF-kappa-B signaling. DAB2IP acts as a negative regulator in the IFN-gamma-mediated JAK-STAT signaling cascade by inhibiting smooth muscle cell (VSMCs) proliferation and intimal expansion, thus preventing graft arteriosclerosis (GA). It acts as a GTPase-activating protein (GAP) for the ADP ribosylation factor 6 (ARF6) and Ras, promoting the hydrolysis of the ARF6-bound GTP and negatively regulating phosphatidylinositol 4,5-bisphosphate (PIP2)-dependent TLR4-TIRAP-MyD88 and NF-kappa-B signaling pathways in endothelial cells in response to lipopolysaccharides (LPS). DAB2IP specifically binds to phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 3-phosphate (PtdIns3P). In response to vascular endothelial growth factor (VEGFA), it 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, DAB2IP promotes 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. It is a probable downstream effector of the Reelin signaling pathway, promoting Purkinje cell (PC) dendrites development and formation of cerebellar synapses. DAB2IP also functions as a tumor suppressor protein in prostate cancer progression, preventing 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.
DAB2IP is also known as AF9Q34, AIP-1, AIP1, DIP1/2.
