InnateDB: Systems Biology of the Innate Immune Response

Mus musculus Protein: Dab2ip

Summary

InnateDB Protein

IDBP-254804.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

Dab2ip

Protein Name

disabled homolog 2 (Drosophila) interacting protein

Synonyms

2310011D08Rik; AI480459; Aip1; mKIAA1743;

Species

Mus musculus

Ensembl Protein

ENSMUSP00000108616

InnateDB Gene

IDBG-164698 (Dab2ip)

Protein Structure

UniProt Annotation

Function

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. {ECO:0000269PubMed:18281285, ECO:0000269PubMed:19033661, ECO:0000269PubMed:19903888, ECO:0000269PubMed:19948740, ECO:0000269PubMed:20080667, ECO:0000269PubMed:20154697, ECO:0000269PubMed:21700930, ECO:0000269PubMed:22696229, ECO:0000269PubMed:23056358, ECO:0000269PubMed:23326475}.

Subcellular Localization

Cytoplasm. Cell membrane {ECO:0000305}; Peripheral membrane protein {ECO:0000305}. Cell projection, dendrite. Note=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 (By similarity). Localized in soma and dendrites of Purkinje cells as well as in scattered cell bodies in the molecular layer of the cerebellum. {ECO:0000250}.

Disease Associations

Tissue Specificity

Expressed in vascular endothelium of muscle and aorta, in smooth muscle cells of aorta and epithelial cells of lung. Expressed throughout the brain, including olfactory bulb, hypothalamus, cerebellum and cerebral cortex. Expressed in the soma and processes of neurons in a variety of brain structures, including the developing cerebral cortex, CA1 pyramidal neurons and Purkinje cells. Poorly expressed in medulloblastoma cells compared to cerebellar precursor proliferating progenitor cells (at protein level). Highly expressed in the brain, salivary gland, and testis; moderate expression in kidney and heart. Low expression in the lung, seminal vesicle, ventral prostate, epididymis, liver, and bladder. Very low expression in the coagulation gland and skeleton muscles. Lowest expression seen in spleen. {ECO:0000269PubMed:12877983, ECO:0000269PubMed:16629596, ECO:0000269PubMed:19033661, ECO:0000269PubMed:22696229, ECO:0000269PubMed:23326475}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 1 experimentally validated interaction(s) in this database.
They are also associated with 13 interaction(s) predicted by orthology.

Experimentally validated
Total	1 [view]
Protein-Protein	1 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	13 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0005096	GTPase activator activity
GO:0005099	Ras GTPase activator activity
GO:0005123	death receptor binding
GO:0005515	protein binding
GO:0017124	SH3 domain binding
GO:0031434	mitogen-activated protein kinase kinase binding
GO:0031435	mitogen-activated protein kinase kinase kinase binding
GO:0032266	phosphatidylinositol-3-phosphate binding
GO:0032403	protein complex binding
GO:0035591	signaling adaptor activity
GO:0036312	phosphatidylinositol 3-kinase regulatory subunit binding
GO:0042803	protein homodimerization activity
GO:0043184	vascular endothelial growth factor receptor 2 binding
GO:0043548	phosphatidylinositol 3-kinase binding
GO:0047485	protein N-terminus binding
GO:0051721	protein phosphatase 2A binding
GO:0070273	phosphatidylinositol-4-phosphate binding
GO:0071889	14-3-3 protein binding

Biological Process

GO:0000122	negative regulation of transcription from RNA polymerase II promoter
GO:0000185	activation of MAPKKK activity
GO:0001525	angiogenesis
GO:0001933	negative regulation of protein phosphorylation
GO:0006954	inflammatory response
GO:0006986	response to unfolded protein
GO:0007049	cell cycle
GO:0007165	signal transduction
GO:0007252	I-kappaB phosphorylation
GO:0007257	activation of JUN kinase activity
GO:0008285	negative regulation of cell proliferation
GO:0008625	extrinsic apoptotic signaling pathway via death domain receptors
GO:0010596	negative regulation of endothelial cell migration
GO:0010633	negative regulation of epithelial cell migration
GO:0010719	negative regulation of epithelial to mesenchymal transition
GO:0010976	positive regulation of neuron projection development
GO:0014067	negative regulation of phosphatidylinositol 3-kinase signaling
GO:0016525	negative regulation of angiogenesis
GO:0021814	cell motility involved in cerebral cortex radial glia guided migration
GO:0021819	layer formation in cerebral cortex
GO:0030308	negative regulation of cell growth
GO:0030948	negative regulation of vascular endothelial growth factor receptor signaling pathway
GO:0032088	negative regulation of NF-kappaB transcription factor activity
GO:0032312	regulation of ARF GTPase activity
GO:0032320	positive regulation of Ras GTPase activity
GO:0034144	negative regulation of toll-like receptor 4 signaling pathway
GO:0034260	negative regulation of GTPase activity
GO:0034261	negative regulation of Ras GTPase activity
GO:0035148	tube formation
GO:0035414	negative regulation of catenin import into nucleus
GO:0035924	cellular response to vascular endothelial growth factor stimulus
GO:0036324	vascular endothelial growth factor receptor-2 signaling pathway
GO:0042059	negative regulation of epidermal growth factor receptor signaling pathway
GO:0043065	positive regulation of apoptotic process
GO:0043122	regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043124	negative regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043254	regulation of protein complex assembly
GO:0043407	negative regulation of MAP kinase activity
GO:0043410	positive regulation of MAPK cascade
GO:0043507	positive regulation of JUN kinase activity
GO:0043553	negative regulation of phosphatidylinositol 3-kinase activity
GO:0044257	cellular protein catabolic process
GO:0045087	innate immune response
GO:0045732	positive regulation of protein catabolic process
GO:0045892	negative regulation of transcription, DNA-templated
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0046330	positive regulation of JNK cascade
GO:0046580	negative regulation of Ras protein signal transduction
GO:0048147	negative regulation of fibroblast proliferation
GO:0048812	neuron projection morphogenesis
GO:0050679	positive regulation of epithelial cell proliferation
GO:0050680	negative regulation of epithelial cell proliferation
GO:0051056	regulation of small GTPase mediated signal transduction
GO:0070059	intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
GO:0070317	negative regulation of G0 to G1 transition
GO:0070373	negative regulation of ERK1 and ERK2 cascade
GO:0071158	positive regulation of cell cycle arrest
GO:0071222	cellular response to lipopolysaccharide
GO:0071347	cellular response to interleukin-1
GO:0071356	cellular response to tumor necrosis factor
GO:0071364	cellular response to epidermal growth factor stimulus
GO:0071901	negative regulation of protein serine/threonine kinase activity
GO:0071902	positive regulation of protein serine/threonine kinase activity
GO:0090090	negative regulation of canonical Wnt signaling pathway
GO:0090129	positive regulation of synapse maturation
GO:1900006	positive regulation of dendrite development
GO:1900744	regulation of p38MAPK cascade
GO:1900747	negative regulation of vascular endothelial growth factor signaling pathway
GO:1901800	positive regulation of proteasomal protein catabolic process
GO:2000599	negative regulation of cyclin catabolic process
GO:2001224	positive regulation of neuron migration
GO:2001235	positive regulation of apoptotic signaling pathway

Cellular Component

GO:0005622	intracellular
GO:0005737	cytoplasm
GO:0005886	plasma membrane
GO:0030139	endocytic vesicle
GO:0030424	axon
GO:0030425	dendrite
GO:0031235	intrinsic component of the cytoplasmic side of the plasma membrane
GO:0032809	neuronal cell body membrane
GO:0043025	neuronal cell body
GO:0044300	cerebellar mossy fiber
GO:0044301	climbing fiber
GO:1990032	parallel fiber

Protein Structure and Domains

PDB ID

MGI:1916851

InterPro

IPR000008 C2 domain
IPR001849 Pleckstrin homology domain
IPR001936 Ras GTPase-activating protein
IPR008936 Rho GTPase activation protein
IPR021887 Protein of unknown function DUF3498

PFAM

PF00168
PF00169
PF00616
PF12004

PRINTS

PR00360

PIRSF

SMART

SM00239
SM00233
SM00323

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt