DAB2P_HUMAN
ID DAB2P_HUMAN Reviewed; 1189 AA.
AC Q5VWQ8; A6H8V2; A6NHI9; B0QZB1; G3XA90; Q8TDL2; Q96SE1; Q9C0C0;
DT 17-OCT-2006, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 169.
DE RecName: Full=Disabled homolog 2-interacting protein;
DE Short=DAB2 interaction protein;
DE Short=DAB2-interacting protein;
DE AltName: Full=ASK-interacting protein 1;
DE Short=AIP-1;
DE AltName: Full=DOC-2/DAB-2 interactive protein;
GN Name=DAB2IP; Synonyms=AF9Q34, AIP1, KIAA1743;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), AND TISSUE SPECIFICITY.
RX PubMed=11944990; DOI=10.1006/geno.2002.6739;
RA Chen H., Pong R.-C., Wang Z., Hsieh J.-T.;
RT "Differential regulation of the human gene DAB2IP in normal and malignant
RT prostatic epithelia: cloning and characterization.";
RL Genomics 79:573-581(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND CHROMOSOMAL TRANSLOCATION WITH
RP KMT2A/MLL1.
RX PubMed=14978793; DOI=10.1002/gcc.20004;
RA von Bergh A.R.M., Wijers P.M., Groot A.J., van Zelderen-Bhola S.,
RA Falkenburg J.H.F., Kluin P.M., Schuuring E.;
RT "Identification of a novel RAS GTPase-activating protein (RASGAP) gene at
RT 9q34 as an MLL fusion partner in a patient with de novo acute myeloid
RT leukemia.";
RL Genes Chromosomes Cancer 39:324-334(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Brain;
RX PubMed=11214970; DOI=10.1093/dnares/7.6.347;
RA Nagase T., Kikuno R., Hattori A., Kondo Y., Okumura K., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIX. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 7:347-355(2000).
RN [4]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION, INTERACTION WITH MAP3K5, AND MUTAGENESIS OF 228-LYS--LYS-230;
RP 281-LYS--LYS-284 AND ARG-413.
RX PubMed=12813029; DOI=10.1172/jci200317790;
RA Zhang R., He X., Liu W., Lu M., Hsieh J.-T., Min W.;
RT "AIP1 mediates TNF-alpha-induced ASK1 activation by facilitating
RT dissociation of ASK1 from its inhibitor 14-3-3.";
RL J. Clin. Invest. 111:1933-1943(2003).
RN [9]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH TNFR1; MAP3K5; TRADD; RIPK1 AND
RP TRAF2.
RX PubMed=15310755; DOI=10.1074/jbc.m407617200;
RA Zhang H., Zhang R., Luo Y., D'Alessio A., Pober J.S., Min W.;
RT "AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-
RT induced ASK1-JNK activation.";
RL J. Biol. Chem. 279:44955-44965(2004).
RN [10]
RP INTERACTION WITH HIPK1, AND SUBCELLULAR LOCATION.
RX PubMed=15701637; DOI=10.1074/jbc.m414262200;
RA Li X., Zhang R., Luo D., Park S.-J., Wang Q., Kim Y., Min W.;
RT "Tumor necrosis factor alpha-induced desumoylation and cytoplasmic
RT translocation of homeodomain-interacting protein kinase 1 are critical for
RT apoptosis signal-regulating kinase 1-JNK/p38 activation.";
RL J. Biol. Chem. 280:15061-15070(2005).
RN [11]
RP FUNCTION, INTERACTION WITH 14-3-3 PROTEINS; MAP3K5; RIPK1 AND TRAF2,
RP PHOSPHORYLATION AT SER-728, MUTAGENESIS OF SER-728 AND THR-935, AND TISSUE
RP SPECIFICITY.
RX PubMed=17389591; DOI=10.1074/jbc.m701148200;
RA Zhang H., Zhang H., Lin Y., Li J., Pober J.S., Min W.;
RT "RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical
RT for tumor necrosis factor-induced ASK1-JNK/p38 activation.";
RL J. Biol. Chem. 282:14788-14796(2007).
RN [12]
RP FUNCTION, AND MUTAGENESIS OF SER-728.
RX PubMed=18292600; DOI=10.1161/circresaha.107.168153;
RA Min W., Lin Y., Tang S., Yu L., Zhang H., Wan T., Luhn T., Fu H., Chen H.;
RT "AIP1 recruits phosphatase PP2A to ASK1 in tumor necrosis factor-induced
RT ASK1-JNK activation.";
RL Circ. Res. 102:840-848(2008).
RN [13]
RP FUNCTION, INTERACTION WITH KDR AND P85 SUBUNIT OF PI3K, AND MUTAGENESIS OF
RP 228-LYS--LYS-230 AND 281-LYS--LYS-284.
RX PubMed=19033661; DOI=10.1172/jci36168;
RA Zhang H., He Y., Dai S., Xu Z., Luo Y., Wan T., Luo D., Jones D., Tang S.,
RA Chen H., Sessa W.C., Min W.;
RT "AIP1 functions as an endogenous inhibitor of VEGFR2-mediated signaling and
RT inflammatory angiogenesis in mice.";
RL J. Clin. Invest. 118:3904-3916(2008).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [15]
RP FUNCTION, INTERACTION WITH AKT1 AND P85 SUBUNIT OF PI3K, PHOSPHORYLATION AT
RP SER-728, AND MUTAGENESIS OF ARG-413; SER-728 AND 920-PRO--PRO-929.
RX PubMed=19903888; DOI=10.1073/pnas.0908458106;
RA Xie D., Gore C., Zhou J., Pong R.C., Zhang H., Yu L., Vessella R.L.,
RA Min W., Hsieh J.T.;
RT "DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and
RT apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:19878-19883(2009).
RN [16]
RP FUNCTION, INTERACTION WITH PHOSPHATIDYLINOSITOL, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF ARG-413.
RX PubMed=19948740; DOI=10.1074/jbc.m109.069385;
RA Wan T., Liu T., Zhang H., Tang S., Min W.;
RT "AIP1 functions as Arf6-GAP to negatively regulate TLR4 signaling.";
RL J. Biol. Chem. 285:3750-3757(2010).
RN [17]
RP FUNCTION IN PROSTATE CANCER, INDUCTION, AND MUTAGENESIS OF ARG-413 AND
RP SER-728.
RX PubMed=20154697; DOI=10.1038/nm.2100;
RA Min J., Zaslavsky A., Fedele G., McLaughlin S.K., Reczek E.E., De Raedt T.,
RA Guney I., Strochlic D.E., Macconaill L.E., Beroukhim R., Bronson R.T.,
RA Ryeom S., Hahn W.C., Loda M., Cichowski K.;
RT "An oncogene-tumor suppressor cascade drives metastatic prostate cancer by
RT coordinately activating Ras and nuclear factor-kappaB.";
RL Nat. Med. 16:286-294(2010).
RN [18]
RP FUNCTION IN PROSTATE CANCER, AND INTERACTION WITH GSK3B AND PPP2CA.
RX PubMed=20080667; DOI=10.1073/pnas.0908133107;
RA Xie D., Gore C., Liu J., Pong R.C., Mason R., Hao G., Long M., Kabbani W.,
RA Yu L., Zhang H., Chen H., Sun X., Boothman D.A., Min W., Hsieh J.T.;
RT "Role of DAB2IP in modulating epithelial-to-mesenchymal transition and
RT prostate cancer metastasis.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:2485-2490(2010).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP FUNCTION, INTERACTION WITH JAK2, AND TISSUE SPECIFICITY.
RX PubMed=21700930; DOI=10.1161/circresaha.111.248245;
RA Yu L., Qin L., Zhang H., He Y., Chen H., Pober J.S., Tellides G., Min W.;
RT "AIP1 prevents graft arteriosclerosis by inhibiting interferon-gamma-
RT dependent smooth muscle cell proliferation and intimal expansion.";
RL Circ. Res. 109:418-427(2011).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-978, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [22]
RP FUNCTION IN MEDULLOBLASTOMA DEVELOPMENT, INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=22696229; DOI=10.1158/1078-0432.ccr-12-0399;
RA Smits M., van Rijn S., Hulleman E., Biesmans D., van Vuurden D.G., Kool M.,
RA Haberler C., Aronica E., Vandertop W.P., Noske D.P., Wurdinger T.;
RT "EZH2-regulated DAB2IP is a medulloblastoma tumor suppressor and a positive
RT marker for survival.";
RL Clin. Cancer Res. 18:4048-4058(2012).
RN [23]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-747; SER-978 AND SER-995, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
CC -!- FUNCTION: Functions as a scaffold protein implicated in the regulation
CC of a large spectrum of both general and specialized signaling pathways.
CC Involved in several processes such as innate immune response,
CC inflammation and cell growth inhibition, apoptosis, cell survival,
CC angiogenesis, cell migration and maturation. Also plays a role in cell
CC cycle checkpoint control; reduces G1 phase cyclin levels resulting in
CC G0/G1 cell cycle arrest. Mediates signal transduction by receptor-
CC mediated inflammatory signals, such as the tumor necrosis factor (TNF),
CC interferon (IFN) or lipopolysaccharide (LPS). Modulates the balance
CC between phosphatidylinositol 3-kinase (PI3K)-AKT-mediated cell survival
CC and apoptosis stimulated kinase (MAP3K5)-JNK signaling pathways;
CC sequesters both AKT1 and MAP3K5 and counterbalances the activity of
CC each kinase by modulating their phosphorylation status in response to
CC pro-inflammatory stimuli. Acts as a regulator of the endoplasmic
CC reticulum (ER) unfolded protein response (UPR) pathway; specifically
CC involved in transduction of the ER stress-response to the JNK cascade
CC through ERN1. Mediates TNF-alpha-induced apoptosis activation by
CC facilitating dissociation of inhibitor 14-3-3 from MAP3K5; recruits the
CC PP2A phosphatase complex which dephosphorylates MAP3K5 on 'Ser-966',
CC leading to the dissociation of 13-3-3 proteins and activation of the
CC MAP3K5-JNK signaling pathway in endothelial cells. Mediates also
CC TNF/TRAF2-induced MAP3K5-JNK activation, while it inhibits CHUK-NF-
CC kappa-B signaling. Acts a negative regulator in the IFN-gamma-mediated
CC JAK-STAT signaling cascade by inhibiting smooth muscle cell (VSMCs)
CC proliferation and intimal expansion, and thus, prevents graft
CC arteriosclerosis (GA). Acts as a GTPase-activating protein (GAP) for
CC the ADP ribosylation factor 6 (ARF6) and Ras. Promotes hydrolysis of
CC the ARF6-bound GTP and thus, negatively regulates phosphatidylinositol
CC 4,5-bisphosphate (PIP2)-dependent TLR4-TIRAP-MyD88 and NF-kappa-B
CC signaling pathways in endothelial cells in response to
CC lipopolysaccharides (LPS). Binds specifically to phosphatidylinositol
CC 4-phosphate (PtdIns4P) and phosphatidylinositol 3-phosphate (PtdIns3P).
CC In response to vascular endothelial growth factor (VEGFA), acts as a
CC negative regulator of the VEGFR2-PI3K-mediated angiogenic signaling
CC pathway by inhibiting endothelial cell migration and tube formation. In
CC the developing brain, promotes both the transition from the multipolar
CC to the bipolar stage and the radial migration of cortical neurons from
CC the ventricular zone toward the superficial layer of the neocortex in a
CC glial-dependent locomotion process. Probable downstream effector of the
CC Reelin signaling pathway; promotes Purkinje cell (PC) dendrites
CC development and formation of cerebellar synapses. Functions also as a
CC tumor suppressor protein in prostate cancer progression; prevents cell
CC proliferation and epithelial-to-mesenchymal transition (EMT) through
CC activation of the glycogen synthase kinase-3 beta (GSK3B)-induced beta-
CC catenin and inhibition of PI3K-AKT and Ras-MAPK survival downstream
CC signaling cascades, respectively. {ECO:0000269|PubMed:12813029,
CC ECO:0000269|PubMed:17389591, ECO:0000269|PubMed:18292600,
CC ECO:0000269|PubMed:19033661, ECO:0000269|PubMed:19903888,
CC ECO:0000269|PubMed:19948740, ECO:0000269|PubMed:20080667,
CC ECO:0000269|PubMed:20154697, ECO:0000269|PubMed:21700930,
CC ECO:0000269|PubMed:22696229}.
CC -!- SUBUNIT: On plasma membrane, exists in an inactive form complexed with
CC TNFR1; in response to TNF-alpha, dissociates from TNFR1 complex,
CC translocates to cytoplasm and forms part of an intracellular signaling
CC complex comprising TRADD, RIPK1, TRAF2 and MAP3K5. Interacts with DAB1.
CC Interacts (via NPXY motif) with DAB2 (via PID domain). Interacts (via
CC PH domain) with ERN1 (By similarity). Part of a cytoplasmic complex
CC made of HIPK1, DAB2IP and MAP3K5 in response to TNF-alpha; this complex
CC formation promotes MAP3K5-JNK activation and subsequent apoptosis.
CC Interacts (via N-terminal domain) with JAK2; the interaction occurs in
CC a IFNG/IFN-gamma-dependent manner and inhibits JAK2 autophosphorylation
CC activity. Interacts (via C2 domain) with GSK3B; the interaction
CC stimulates GSK3B kinase activation. Interacts (via C2 domain) with
CC PPP2CA. Interacts (via proline-rich motif) with a regulatory p85
CC subunit (via SH3 domain) of the PI3K complex; the interaction inhibits
CC the PI3K-AKT complex activity in a TNF-alpha-dependent manner in
CC prostate cancer (PCa) cells. Interacts with AKT1; the interaction is
CC increased in a TNF-alpha-induced manner. Interacts (via C2 domain and
CC active form preferentially) with KDR/VEGFR2 (tyrosine-phosphorylated
CC active form preferentially); the interaction occurs at the late phase
CC of VEGFA response and inhibits KDR/VEGFR2 activity. Interacts (via N-
CC terminus C2 domain) with MAP3K5 ('Ser-966' dephosphorylated form
CC preferentially); the interaction occurs in a TNF-alpha-induced manner.
CC Interacts (via Ras-GAP domain) with the catalytic subunit of protein
CC phosphatase PP2A; the interaction occurs in resting endothelial cells,
CC is further enhanced by TNF-alpha stimulation and is required to bridge
CC PP2A to MAP3K5. Interacts (via C-terminus PER domain) with TRAF2 (via
CC zinc fingers); the interaction occurs in a TNF-alpha-dependent manner.
CC Interacts with 14-3-3 proteins; the interaction occurs in a TNF-alpha-
CC dependent manner. Interacts (via Ras-GAP domain) with RIPK1 (via kinase
CC domain); the interaction occurs in a TNF-alpha-dependent manner.
CC {ECO:0000250, ECO:0000269|PubMed:12813029, ECO:0000269|PubMed:15310755,
CC ECO:0000269|PubMed:15701637, ECO:0000269|PubMed:17389591,
CC ECO:0000269|PubMed:19033661, ECO:0000269|PubMed:19903888,
CC ECO:0000269|PubMed:19948740, ECO:0000269|PubMed:20080667,
CC ECO:0000269|PubMed:21700930}.
CC -!- INTERACTION:
CC Q5VWQ8; Q5VWQ8: DAB2IP; NbExp=2; IntAct=EBI-2871881, EBI-2871881;
CC Q5VWQ8; P49841: GSK3B; NbExp=2; IntAct=EBI-2871881, EBI-373586;
CC Q5VWQ8; Q99683: MAP3K5; NbExp=2; IntAct=EBI-2871881, EBI-476263;
CC Q5VWQ8-2; O15169: AXIN1; NbExp=2; IntAct=EBI-9543020, EBI-710484;
CC Q5VWQ8-2; P49841: GSK3B; NbExp=2; IntAct=EBI-9543020, EBI-373586;
CC Q5VWQ8-5; Q49AR9: ANKS1A; NbExp=3; IntAct=EBI-12196395, EBI-11954519;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane {ECO:0000305};
CC Peripheral membrane protein {ECO:0000305}. Membrane. Cell projection,
CC dendrite {ECO:0000250}. Note=Localized in soma and dendrites of
CC Purkinje cells as well as in scattered cell bodies in the molecular
CC layer of the cerebellum (By similarity). Colocalizes with TIRAP at the
CC plasma membrane. Colocalizes with ARF6 at the plasma membrane and
CC endocytic vesicles. Translocates from the plasma membrane to the
CC cytoplasm in response to TNF-alpha. Phosphatidylinositol 4-phosphate
CC (PtdIns4P) binding is essential for plasma membrane localization.
CC {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1;
CC IsoId=Q5VWQ8-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q5VWQ8-2; Sequence=VSP_020953;
CC Name=3;
CC IsoId=Q5VWQ8-3; Sequence=VSP_020952, VSP_020954;
CC Name=4;
CC IsoId=Q5VWQ8-4; Sequence=VSP_020953, VSP_020954;
CC Name=5;
CC IsoId=Q5VWQ8-5; Sequence=VSP_047361, VSP_020954;
CC -!- TISSUE SPECIFICITY: Expressed in endothelial and vascular smooth muscle
CC cells (VSMCs). Expressed in prostate epithelial but poorly in prostate
CC cancer cells. Poorly expressed in medulloblastoma cells compared to
CC cerebellar precursor proliferating progenitor cells (at protein level).
CC Low expression in prostate. Down-regulated in prostate cancer.
CC {ECO:0000269|PubMed:11944990, ECO:0000269|PubMed:17389591,
CC ECO:0000269|PubMed:21700930, ECO:0000269|PubMed:22696229}.
CC -!- INDUCTION: Down-regulated in prostate cancer and medulloblastoma.
CC {ECO:0000269|PubMed:20154697, ECO:0000269|PubMed:22696229}.
CC -!- DOMAIN: The C2 and Ras-GAP domains constitutively bind to MAP3K5 and
CC facilitate the release of 14-3-3 proteins from MAP3K5. The PH and Ras-
CC GAP domains, but not the NPXY motif, are crucial for its cell membrane
CC localization and neuronal migration function. The PH domain is
CC necessary but not sufficient to activate the JNK signaling pathway
CC through ERN1 (By similarity). Exists in a closed inactive form by an
CC intramolecular interaction between the N- and the C-terminal domains.
CC The proline-rich motif is critical both for PI3K-AKT activity
CC inhibition and MAP3K5 activation. The PH and C2 domains are necessary
CC for the binding to phosphatidylinositol phosphate. The Ras-GAP domain
CC is necessary for its tumor-suppressive function. {ECO:0000250}.
CC -!- PTM: In response to TNF-alpha-induction, phosphorylated at Ser-728;
CC phosphorylation leads to a conformational change, and thus, increases
CC its association with 14-3-3 proteins, MAP3K5, RIPK1 and TRAF2 in
CC endothelial cells; also stimulates regulatory p85 subunit sequestring
CC and PI3K-p85 complex activity inhibition. {ECO:0000269|PubMed:17389591,
CC ECO:0000269|PubMed:19903888}.
CC -!- DISEASE: Note=A chromosomal aberration involving DAB2IP is found in a
CC patient with acute myeloid leukemia (AML). Translocation
CC t(9;11)(q34;q23) with KMT2A/MLL1. May give rise to a KMT2A/MLL1-DAB2IP
CC fusion protein lacking the PH domain (PubMed:14978793).
CC {ECO:0000269|PubMed:14978793}.
CC -!- MISCELLANEOUS: The DAB2IP gene is found epigenetically silenced in
CC numerous aggressive cancers, like prostate cancers and medulloblastoma
CC tumors. Epigenetic suppression of DAB2IP by EZH2 is a major mechanism
CC of DAB2IP inactivation in human prostate cancer and increases
CC metastatic potential (PubMed:20154697, PubMed:22696229).
CC {ECO:0000305|PubMed:20154697, ECO:0000305|PubMed:22696229}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/AF9q34ID316.html";
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DR EMBL; AF367051; AAM00371.1; -; mRNA.
DR EMBL; AY032952; AAK50336.1; -; mRNA.
DR EMBL; AB051530; BAB21834.2; -; mRNA.
DR EMBL; AL357936; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL365274; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471090; EAW87503.1; -; Genomic_DNA.
DR EMBL; CH471090; EAW87504.1; -; Genomic_DNA.
DR EMBL; BC146762; AAI46763.1; -; mRNA.
DR CCDS; CCDS6832.1; -. [Q5VWQ8-2]
DR CCDS; CCDS6833.2; -. [Q5VWQ8-5]
DR RefSeq; NP_115941.2; NM_032552.3. [Q5VWQ8-5]
DR RefSeq; NP_619723.1; NM_138709.2. [Q5VWQ8-2]
DR RefSeq; XP_005251776.1; XM_005251719.4. [Q5VWQ8-1]
DR RefSeq; XP_011516572.1; XM_011518270.2. [Q5VWQ8-2]
DR RefSeq; XP_011516573.1; XM_011518271.2. [Q5VWQ8-2]
DR RefSeq; XP_016869789.1; XM_017014300.1. [Q5VWQ8-2]
DR AlphaFoldDB; Q5VWQ8; -.
DR SMR; Q5VWQ8; -.
DR BioGRID; 127478; 72.
DR DIP; DIP-41721N; -.
DR IntAct; Q5VWQ8; 23.
DR MINT; Q5VWQ8; -.
DR STRING; 9606.ENSP00000259371; -.
DR ChEMBL; CHEMBL4523330; -.
DR CarbonylDB; Q5VWQ8; -.
DR iPTMnet; Q5VWQ8; -.
DR PhosphoSitePlus; Q5VWQ8; -.
DR BioMuta; DAB2IP; -.
DR DMDM; 116247768; -.
DR EPD; Q5VWQ8; -.
DR jPOST; Q5VWQ8; -.
DR MassIVE; Q5VWQ8; -.
DR MaxQB; Q5VWQ8; -.
DR PaxDb; Q5VWQ8; -.
DR PeptideAtlas; Q5VWQ8; -.
DR PRIDE; Q5VWQ8; -.
DR ProteomicsDB; 33682; -.
DR ProteomicsDB; 65554; -. [Q5VWQ8-1]
DR ProteomicsDB; 65555; -. [Q5VWQ8-2]
DR ProteomicsDB; 65556; -. [Q5VWQ8-3]
DR ProteomicsDB; 65557; -. [Q5VWQ8-4]
DR Antibodypedia; 48362; 112 antibodies from 21 providers.
DR DNASU; 153090; -.
DR Ensembl; ENST00000259371.7; ENSP00000259371.2; ENSG00000136848.18. [Q5VWQ8-5]
DR Ensembl; ENST00000309989.1; ENSP00000310827.1; ENSG00000136848.18. [Q5VWQ8-2]
DR Ensembl; ENST00000408936.7; ENSP00000386183.3; ENSG00000136848.18. [Q5VWQ8-1]
DR GeneID; 153090; -.
DR KEGG; hsa:153090; -.
DR MANE-Select; ENST00000408936.8; ENSP00000386183.3; NM_001395010.1; NP_001381939.1.
DR UCSC; uc004bln.5; human. [Q5VWQ8-1]
DR CTD; 153090; -.
DR DisGeNET; 153090; -.
DR GeneCards; DAB2IP; -.
DR HGNC; HGNC:17294; DAB2IP.
DR HPA; ENSG00000136848; Low tissue specificity.
DR MIM; 609205; gene.
DR neXtProt; NX_Q5VWQ8; -.
DR OpenTargets; ENSG00000136848; -.
DR PharmGKB; PA27133; -.
DR VEuPathDB; HostDB:ENSG00000136848; -.
DR eggNOG; KOG3508; Eukaryota.
DR GeneTree; ENSGT00940000155853; -.
DR HOGENOM; CLU_001727_1_0_1; -.
DR InParanoid; Q5VWQ8; -.
DR OMA; TPFRVTX; -.
DR OrthoDB; 69536at2759; -.
DR PhylomeDB; Q5VWQ8; -.
DR TreeFam; TF105303; -.
DR PathwayCommons; Q5VWQ8; -.
DR Reactome; R-HSA-5658442; Regulation of RAS by GAPs.
DR SignaLink; Q5VWQ8; -.
DR SIGNOR; Q5VWQ8; -.
DR BioGRID-ORCS; 153090; 14 hits in 1070 CRISPR screens.
DR ChiTaRS; DAB2IP; human.
DR GeneWiki; DAB2IP; -.
DR GenomeRNAi; 153090; -.
DR Pharos; Q5VWQ8; Tchem.
DR PRO; PR:Q5VWQ8; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; Q5VWQ8; protein.
DR Bgee; ENSG00000136848; Expressed in right hemisphere of cerebellum and 177 other tissues.
DR ExpressionAtlas; Q5VWQ8; baseline and differential.
DR Genevisible; Q5VWQ8; HS.
DR GO; GO:1990597; C:AIP1-IRE1 complex; IDA:ParkinsonsUK-UCL.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0044300; C:cerebellar mossy fiber; ISS:UniProtKB.
DR GO; GO:0044301; C:climbing fiber; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell.
DR GO; GO:0030139; C:endocytic vesicle; IDA:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; ISS:UniProtKB.
DR GO; GO:0032809; C:neuronal cell body membrane; ISS:UniProtKB.
DR GO; GO:1990032; C:parallel fiber; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0071889; F:14-3-3 protein binding; IDA:BHF-UCL.
DR GO; GO:0045296; F:cadherin binding; HDA:BHF-UCL.
DR GO; GO:0005123; F:death receptor binding; IPI:BHF-UCL.
DR GO; GO:0005096; F:GTPase activator activity; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0019900; F:kinase binding; IPI:UniProtKB.
DR GO; GO:0031434; F:mitogen-activated protein kinase kinase binding; IPI:UniProtKB.
DR GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; IPI:BHF-UCL.
DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; IDA:UniProtKB.
DR GO; GO:0036312; F:phosphatidylinositol 3-kinase regulatory subunit binding; IDA:UniProtKB.
DR GO; GO:0032266; F:phosphatidylinositol-3-phosphate binding; IDA:UniProtKB.
DR GO; GO:0070273; F:phosphatidylinositol-4-phosphate binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:BHF-UCL.
DR GO; GO:0019901; F:protein kinase binding; IDA:ParkinsonsUK-UCL.
DR GO; GO:0051721; F:protein phosphatase 2A binding; IDA:BHF-UCL.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; IDA:GO_Central.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:UniProtKB.
DR GO; GO:0017124; F:SH3 domain binding; IDA:UniProtKB.
DR GO; GO:0035591; F:signaling adaptor activity; IDA:GO_Central.
DR GO; GO:0043184; F:vascular endothelial growth factor receptor 2 binding; IPI:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0007049; P:cell cycle; IEA:UniProtKB-KW.
DR GO; GO:0021814; P:cell motility involved in cerebral cortex radial glia guided migration; ISS:UniProtKB.
DR GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; ISS:BHF-UCL.
DR GO; GO:0071347; P:cellular response to interleukin-1; IDA:UniProtKB.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IDA:UniProtKB.
DR GO; GO:0071356; P:cellular response to tumor necrosis factor; IDA:UniProtKB.
DR GO; GO:0034620; P:cellular response to unfolded protein; TAS:ParkinsonsUK-UCL.
DR GO; GO:0035924; P:cellular response to vascular endothelial growth factor stimulus; IDA:UniProtKB.
DR GO; GO:0072577; P:endothelial cell apoptotic process; TAS:BHF-UCL.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IMP:BHF-UCL.
DR GO; GO:0007252; P:I-kappaB phosphorylation; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; ISS:BHF-UCL.
DR GO; GO:0021819; P:layer formation in cerebral cortex; ISS:UniProtKB.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IDA:UniProtKB.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IMP:BHF-UCL.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:UniProtKB.
DR GO; GO:0010596; P:negative regulation of endothelial cell migration; IMP:UniProtKB.
DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; ISS:BHF-UCL.
DR GO; GO:0010633; P:negative regulation of epithelial cell migration; IMP:UniProtKB.
DR GO; GO:0050680; P:negative regulation of epithelial cell proliferation; IMP:BHF-UCL.
DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; IDA:UniProtKB.
DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IDA:UniProtKB.
DR GO; GO:0048147; P:negative regulation of fibroblast proliferation; ISS:BHF-UCL.
DR GO; GO:0070317; P:negative regulation of G0 to G1 transition; IDA:UniProtKB.
DR GO; GO:0034260; P:negative regulation of GTPase activity; IMP:BHF-UCL.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; IDA:UniProtKB.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IDA:BHF-UCL.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:BHF-UCL.
DR GO; GO:0043553; P:negative regulation of phosphatidylinositol 3-kinase activity; IDA:UniProtKB.
DR GO; GO:0014067; P:negative regulation of phosphatidylinositol 3-kinase signaling; IDA:UniProtKB.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; IDA:UniProtKB.
DR GO; GO:0001933; P:negative regulation of protein phosphorylation; IMP:UniProtKB.
DR GO; GO:0071901; P:negative regulation of protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0046580; P:negative regulation of Ras protein signal transduction; IC:BHF-UCL.
DR GO; GO:0034144; P:negative regulation of toll-like receptor 4 signaling pathway; IDA:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:BHF-UCL.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IMP:UniProtKB.
DR GO; GO:0030948; P:negative regulation of vascular endothelial growth factor receptor signaling pathway; IMP:UniProtKB.
DR GO; GO:1900747; P:negative regulation of vascular endothelial growth factor signaling pathway; ISS:UniProtKB.
DR GO; GO:0048812; P:neuron projection morphogenesis; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:2001235; P:positive regulation of apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:1900006; P:positive regulation of dendrite development; ISS:UniProtKB.
DR GO; GO:1903896; P:positive regulation of IRE1-mediated unfolded protein response; TAS:ParkinsonsUK-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProtKB.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IDA:BHF-UCL.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:UniProtKB.
DR GO; GO:2001224; P:positive regulation of neuron migration; ISS:UniProtKB.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISS:UniProtKB.
DR GO; GO:1901800; P:positive regulation of proteasomal protein catabolic process; IMP:UniProtKB.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; ISS:UniProtKB.
DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; IDA:UniProtKB.
DR GO; GO:0031334; P:positive regulation of protein-containing complex assembly; IDA:ParkinsonsUK-UCL.
DR GO; GO:0090129; P:positive regulation of synapse maturation; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0030163; P:protein catabolic process; IDA:UniProtKB.
DR GO; GO:0038026; P:reelin-mediated signaling pathway; IEA:InterPro.
DR GO; GO:0051726; P:regulation of cell cycle; IDA:UniProtKB.
DR GO; GO:0040008; P:regulation of growth; IEA:UniProtKB-KW.
DR GO; GO:0043087; P:regulation of GTPase activity; ISS:UniProtKB.
DR GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:1900744; P:regulation of p38MAPK cascade; ISS:UniProtKB.
DR GO; GO:0043254; P:regulation of protein-containing complex assembly; IDA:UniProtKB.
DR GO; GO:0035148; P:tube formation; IMP:UniProtKB.
DR GO; GO:0036324; P:vascular endothelial growth factor receptor-2 signaling pathway; ISS:UniProtKB.
DR Gene3D; 1.10.506.10; -; 2.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 2.60.40.150; -; 1.
DR InterPro; IPR000008; C2_dom.
DR InterPro; IPR035892; C2_domain_sf.
DR InterPro; IPR030403; DAB2IP.
DR InterPro; IPR021887; DAB2P_C.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR001849; PH_domain.
DR InterPro; IPR039360; Ras_GTPase.
DR InterPro; IPR023152; RasGAP_CS.
DR InterPro; IPR001936; RasGAP_dom.
DR InterPro; IPR008936; Rho_GTPase_activation_prot.
DR PANTHER; PTHR10194; PTHR10194; 1.
DR PANTHER; PTHR10194:SF26; PTHR10194:SF26; 1.
DR Pfam; PF00168; C2; 1.
DR Pfam; PF12004; DUF3498; 1.
DR Pfam; PF00616; RasGAP; 2.
DR SMART; SM00239; C2; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00323; RasGAP; 1.
DR SUPFAM; SSF48350; SSF48350; 1.
DR SUPFAM; SSF49562; SSF49562; 1.
DR PROSITE; PS50004; C2; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS00509; RAS_GTPASE_ACTIV_1; 1.
DR PROSITE; PS50018; RAS_GTPASE_ACTIV_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Angiogenesis; Apoptosis; Cell cycle; Cell membrane;
KW Cell projection; Chromosomal rearrangement; Coiled coil; Cytoplasm;
KW Developmental protein; Growth regulation; GTPase activation; Immunity;
KW Inflammatory response; Innate immunity; Membrane; Phosphoprotein;
KW Reference proteome; Stress response; Tumor suppressor;
KW Unfolded protein response.
FT CHAIN 1..1189
FT /note="Disabled homolog 2-interacting protein"
FT /id="PRO_0000252407"
FT DOMAIN 101..202
FT /note="PH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
FT DOMAIN 193..311
FT /note="C2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00041"
FT DOMAIN 371..563
FT /note="Ras-GAP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00167"
FT REGION 1..75
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 646..943
FT /note="Necessary for interaction with AKT1"
FT /evidence="ECO:0000269|PubMed:19903888"
FT REGION 653..678
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 715..742
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 803..823
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 843..865
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 895..998
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1015..1035
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1164..1189
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 1026..1159
FT /evidence="ECO:0000255"
FT COMPBIAS 50..66
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 715..735
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 849..865
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 897..915
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 916..935
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 937..978
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1019..1035
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 172..173
FT /note="Breakpoint for translocation to form KMT2A/MLL1-
FT DAB2IP"
FT MOD_RES 728
FT /note="Phosphoserine; by MAP3K5 and RIPK1"
FT /evidence="ECO:0000269|PubMed:17389591,
FT ECO:0000269|PubMed:19903888"
FT MOD_RES 747
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 978
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 995
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 1..193
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:11944990"
FT /id="VSP_020952"
FT VAR_SEQ 1..124
FT /note="Missing (in isoform 2 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:11214970,
FT ECO:0000303|PubMed:14978793, ECO:0000303|PubMed:15489334"
FT /id="VSP_020953"
FT VAR_SEQ 2..41
FT /note="SAGGSARKSTGRSSYYYRLLRRPRLQRQRSRSRSRTRPAR -> EPDSLLDQ
FT DDSY (in isoform 5)"
FT /evidence="ECO:0000305"
FT /id="VSP_047361"
FT VAR_SEQ 1158..1189
FT /note="RYSMQARNGISPTNPTKLQITENGEFRNSSNC -> SMH (in isoform
FT 3, isoform 4 and isoform 5)"
FT /evidence="ECO:0000303|PubMed:11214970,
FT ECO:0000303|PubMed:11944990, ECO:0000303|PubMed:15489334"
FT /id="VSP_020954"
FT VARIANT 59
FT /note="S -> F (in dbSNP:rs7027492)"
FT /id="VAR_056858"
FT MUTAGEN 228..230
FT /note="KKK->AAA: Reduces interaction with KDR/VEGFR2. Does
FT not inhibit interaction with MAP3K5."
FT /evidence="ECO:0000269|PubMed:12813029,
FT ECO:0000269|PubMed:19033661"
FT MUTAGEN 281..284
FT /note="KKKK->AAAA: Significantly reduces interaction with
FT MAP3K5. Does not reduce interaction with KDR/VEGFR2."
FT /evidence="ECO:0000269|PubMed:12813029,
FT ECO:0000269|PubMed:19033661"
FT MUTAGEN 413
FT /note="R->L: Does not inhibit interaction with MAP3K5. Does
FT not reduce GSK3B-induced beta-catenin transcription
FT activity, TNF-alpha-induced apoptosis, ARF6-mediated TLR4-
FT TIRAP-MyD88 signaling inhibition, Ras and NF-kappa-B
FT activities and tumor development. Does not suppress tumor
FT development; when associated with A-728."
FT /evidence="ECO:0000269|PubMed:12813029,
FT ECO:0000269|PubMed:19903888, ECO:0000269|PubMed:19948740,
FT ECO:0000269|PubMed:20154697"
FT MUTAGEN 728
FT /note="S->A: Inhibits phosphorylation and TNF-alpha-induced
FT MAP3K5 dephosphorylation. Reduces interaction with 14-3-3
FT proteins, AKT1, a regulatory p85 subunit, MAP3K5, RIPK1,
FT TRAF2 and TNF-alpha-induced MAP3K5-JNK signaling and
FT apoptosis. Reduces RAS activity. Does not reduce GSK3B-
FT induced beta catenin-mediated transcription activity. Does
FT not reduce NF-kappa-B activity, cell invasion, epithelial-
FT to-mesenchymal transition (EMT) and tumor development. Does
FT not suppress tumor development; when associated with R-
FT 413."
FT /evidence="ECO:0000269|PubMed:17389591,
FT ECO:0000269|PubMed:18292600, ECO:0000269|PubMed:19903888,
FT ECO:0000269|PubMed:20154697"
FT MUTAGEN 920..929
FT /note="PPPPPPPPPP->AAAAAAAAAA: Reduces interaction with a
FT regulatory p85 subunit of the PI3K complex. Inhibits MAP3K5
FT active form increase, AKT1 active form decrease, PI3K-p85
FT complex activity inhibition and TNF-induced apoptosis."
FT /evidence="ECO:0000269|PubMed:19903888"
FT MUTAGEN 935
FT /note="T->A: Does not reduce interaction with 14-3-3
FT proteins."
FT /evidence="ECO:0000269|PubMed:17389591"
FT CONFLICT 482
FT /note="I -> T (in Ref. 1; AAM00371)"
FT /evidence="ECO:0000305"
FT CONFLICT 921
FT /note="P -> S (in Ref. 1; AAM00371)"
FT /evidence="ECO:0000305"
FT CONFLICT 1091..1092
FT /note="QQ -> HE (in Ref. 1; AAM00371)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1189 AA; 131625 MW; 7494FF05AACF3320 CRC64;
MSAGGSARKS TGRSSYYYRL LRRPRLQRQR SRSRSRTRPA RESPQERPGS RRSLPGSLSE
KSPSMEPSAA TPFRVTGFLS RRLKGSIKRT KSQPKLDRNH SFRHILPGFR SAAAAAADNE
RSHLMPRLKE SRSHESLLSP SSAVEALDLS MEEEVVIKPV HSSILGQDYC FEVTTSSGSK
CFSCRSAAER DKWMENLRRA VHPNKDNSRR VEHILKLWVI EAKDLPAKKK YLCELCLDDV
LYARTTGKLK TDNVFWGEHF EFHNLPPLRT VTVHLYRETD KKKKKERNSY LGLVSLPAAS
VAGRQFVEKW YPVVTPNPKG GKGPGPMIRI KARYQTITIL PMEMYKEFAE HITNHYLGLC
AALEPILSAK TKEEMASALV HILQSTGKVK DFLTDLMMSE VDRCGDNEHL IFRENTLATK
AIEEYLKLVG QKYLQDALGE FIKALYESDE NCEVDPSKCS AADLPEHQGN LKMCCELAFC
KIINSYCVFP RELKEVFASW RQECSSRGRP DISERLISAS LFLRFLCPAI MSPSLFNLLQ
EYPDDRTART LTLIAKVTQN LANFAKFGSK EEYMSFMNQF LEHEWTNMQR FLLEISNPET
LSNTAGFEGY IDLGRELSSL HSLLWEAVSQ LEQSIVSKLG PLPRILRDVH TALSTPGSGQ
LPGTNDLAST PGSGSSSISA GLQKMVIEND LSGLIDFTRL PSPTPENKDL FFVTRSSGVQ
PSPARSSSYS EANEPDLQMA NGGKSLSMVD LQDARTLDGE AGSPAGPDVL PTDGQAAAAQ
LVAGWPARAT PVNLAGLATV RRAGQTPTTP GTSEGAPGRP QLLAPLSFQN PVYQMAAGLP
LSPRGLGDSG SEGHSSLSSH SNSEELAAAA KLGSFSTAAE ELARRPGELA RRQMSLTEKG
GQPTVPRQNS AGPQRRIDQP PPPPPPPPPA PRGRTPPNLL STLQYPRPSS GTLASASPDW
VGPSTRLRQQ SSSSKGDSPE LKPRAVHKQG PSPVSPNALD RTAAWLLTMN AQLLEDEGLG
PDPPHRDRLR SKDELSQAEK DLAVLQDKLR ISTKKLEEYE TLFKCQEETT QKLVLEYQAR
LEEGEERLRR QQEDKDIQMK GIISRLMSVE EELKKDHAEM QAAVDSKQKI IDAQEKRIAS
LDAANARLMS ALTQLKERYS MQARNGISPT NPTKLQITEN GEFRNSSNC
