ROBO4_MOUSE
ID ROBO4_MOUSE Reviewed; 1012 AA.
AC Q8C310; Q9DBW1;
DT 21-JUN-2004, integrated into UniProtKB/Swiss-Prot.
DT 21-JUN-2004, sequence version 2.
DT 03-AUG-2022, entry version 152.
DE RecName: Full=Roundabout homolog 4;
DE Flags: Precursor;
GN Name=Robo4;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH SLIT2
RP AND ENAH, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC STRAIN=FVB/N;
RX PubMed=12941633; DOI=10.1016/s0012-1606(03)00258-6;
RA Park K.W., Morrison C.M., Sorensen L.K., Jones C.A., Rao Y., Chien C.-B.,
RA Wu J.Y., Urness L.D., Li D.Y.;
RT "Robo4 is a vascular-specific receptor that inhibits endothelial
RT migration.";
RL Dev. Biol. 261:251-267(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC STRAIN=C57BL/6J; TISSUE=Lung;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 475-1012 (ISOFORM 2).
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 [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-947, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, and Lung;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP DEVELOPMENTAL STAGE, AND DISRUPTION PHENOTYPE.
RX PubMed=30455415; DOI=10.1038/s41588-018-0265-y;
RG Baylor-Hopkins Center for Mendelian Genomics;
RG MIBAVA Leducq Consortium;
RA Gould R.A., Aziz H., Woods C.E., Seman-Senderos M.A., Sparks E., Preuss C.,
RA Wuennemann F., Bedja D., Moats C.R., McClymont S.A., Rose R., Sobreira N.,
RA Ling H., MacCarrick G., Kumar A.A., Luyckx I., Cannaerts E.,
RA Verstraeten A., Bjoerk H.M., Lehsau A.C., Jaskula-Ranga V., Lauridsen H.,
RA Shah A.A., Bennett C.L., Ellinor P.T., Lin H., Isselbacher E.M.,
RA Lino Cardenas C.L., Butcher J.T., Hughes G.C., Lindsay M.E., Mertens L.,
RA Franco-Cereceda A., Verhagen J.M.A., Wessels M., Mohamed S.A., Eriksson P.,
RA Mital S., Van Laer L., Loeys B.L., Andelfinger G., McCallion A.S.,
RA Dietz H.C.;
RT "ROBO4 variants predispose individuals to bicuspid aortic valve and
RT thoracic aortic aneurysm.";
RL Nat. Genet. 51:42-50(2019).
CC -!- FUNCTION: Receptor for Slit proteins, at least for SLIT2, and seems to
CC be involved in angiogenesis and vascular patterning. May mediate the
CC inhibition of primary endothelial cell migration by Slit proteins.
CC Involved in the maintenance of endothelial barrier organization and
CC function (By similarity). {ECO:0000250|UniProtKB:Q8WZ75,
CC ECO:0000269|PubMed:12941633}.
CC -!- SUBUNIT: Interacts with SLIT2 and ENAH. {ECO:0000269|PubMed:12941633}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q8C310-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8C310-2; Sequence=VSP_010662;
CC Name=3;
CC IsoId=Q8C310-3; Sequence=VSP_010663, VSP_010662;
CC -!- TISSUE SPECIFICITY: Expressed specifically in embryo and adult vascular
CC endothelium. {ECO:0000269|PubMed:12941633}.
CC -!- DEVELOPMENTAL STAGE: In embryonic development of vascular endothelium,
CC it shows a dynamic expression pattern within vessels, with expression
CC starting in the larger axial vessels and intersomitic vessels at
CC earlier ages, and changing to intersomitic vessel and capillary
CC expression at later stages. At 9.0 dpc, is expressed in the central
CC vessels, the dorsal aorta, and intersomitic vessels. At 9.5 dpc, is
CC highly expressed in intersomitic vessels with little expression
CC remaining in dorsal aortae. By 10.0 dpc, is detected in capillary
CC vessels, the capillary plexus of the limb buds, and throughout the
CC endothelium as microvessels sprout from the dorsal aortae. No
CC expression was detected in the neural tube at 9.0 dpc and 9.5 dpc.
CC However, it is detected within the capillaries sprouting into the
CC neural tube, as well as in the adjacent perineural capillary plexus at
CC 10.0 dpc. At 11.5 dpc, it is expressed in the endocardial layer of the
CC cushions and delamination zones. By 17 dpc, it is detected in both the
CC endothelial and interstitial cells of the developing aortic valve and
CC endothelial cells of the proximal aorta. At 5 weeks after birth, it is
CC localized to the endothelial layer of the ascending aorta and persists
CC throughout postnatal development (PubMed:30455415).
CC {ECO:0000269|PubMed:12941633, ECO:0000269|PubMed:30455415}.
CC -!- DISRUPTION PHENOTYPE: Homozygous knockout mice exhibit a complex
CC cardiovascular phenotype that includes a combination of aortic valve
CC thickening with or without bicuspid aortic valve, aortic valve
CC stenosis, regurgitation and/or ascending aortic aneurysm. In general,
CC these phenotypes are observed with low penetrance and male
CC predominance. {ECO:0000269|PubMed:30455415}.
CC -!- SIMILARITY: Belongs to the immunoglobulin superfamily. ROBO family.
CC {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH20129.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAB23506.2; Type=Erroneous initiation; Evidence={ECO:0000305};
CC -!- SEQUENCE CAUTION: [Isoform 2]:
CC Sequence=AAH20129.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAB23506.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC -!- SEQUENCE CAUTION: [Isoform 3]:
CC Sequence=BAC39850.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAC39850.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AF536772; AAQ10749.1; -; mRNA.
DR EMBL; AK004723; BAB23506.2; ALT_INIT; mRNA.
DR EMBL; AK087355; BAC39850.1; ALT_SEQ; mRNA.
DR EMBL; BC020129; AAH20129.1; ALT_INIT; mRNA.
DR CCDS; CCDS22977.1; -. [Q8C310-2]
DR CCDS; CCDS80976.1; -. [Q8C310-1]
DR RefSeq; NP_001296319.1; NM_001309390.1. [Q8C310-1]
DR RefSeq; NP_083059.2; NM_028783.3. [Q8C310-2]
DR AlphaFoldDB; Q8C310; -.
DR SMR; Q8C310; -.
DR BioGRID; 216523; 3.
DR STRING; 10090.ENSMUSP00000099959; -.
DR GlyGen; Q8C310; 9 sites.
DR iPTMnet; Q8C310; -.
DR PhosphoSitePlus; Q8C310; -.
DR jPOST; Q8C310; -.
DR MaxQB; Q8C310; -.
DR PaxDb; Q8C310; -.
DR PRIDE; Q8C310; -.
DR ProteomicsDB; 301637; -. [Q8C310-1]
DR ProteomicsDB; 301638; -. [Q8C310-2]
DR ProteomicsDB; 301639; -. [Q8C310-3]
DR Antibodypedia; 32921; 444 antibodies from 30 providers.
DR DNASU; 74144; -.
DR Ensembl; ENSMUST00000102895; ENSMUSP00000099959; ENSMUSG00000032125. [Q8C310-2]
DR Ensembl; ENSMUST00000214185; ENSMUSP00000150722; ENSMUSG00000032125. [Q8C310-1]
DR GeneID; 74144; -.
DR KEGG; mmu:74144; -.
DR UCSC; uc009ous.1; mouse. [Q8C310-2]
DR UCSC; uc012gqy.1; mouse. [Q8C310-1]
DR CTD; 54538; -.
DR MGI; MGI:1921394; Robo4.
DR VEuPathDB; HostDB:ENSMUSG00000032125; -.
DR eggNOG; KOG4222; Eukaryota.
DR GeneTree; ENSGT00940000161382; -.
DR InParanoid; Q8C310; -.
DR PhylomeDB; Q8C310; -.
DR TreeFam; TF351053; -.
DR BioGRID-ORCS; 74144; 1 hit in 71 CRISPR screens.
DR ChiTaRS; Robo4; mouse.
DR PRO; PR:Q8C310; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; Q8C310; protein.
DR Bgee; ENSMUSG00000032125; Expressed in interventricular septum and 163 other tissues.
DR ExpressionAtlas; Q8C310; baseline and differential.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:MGI.
DR GO; GO:0016021; C:integral component of membrane; TAS:MGI.
DR GO; GO:0038023; F:signaling receptor activity; IDA:MGI.
DR GO; GO:0001525; P:angiogenesis; ISO:MGI.
DR GO; GO:0043534; P:blood vessel endothelial cell migration; IDA:MGI.
DR GO; GO:0098609; P:cell-cell adhesion; IBA:GO_Central.
DR GO; GO:0061028; P:establishment of endothelial barrier; ISO:MGI.
DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IDA:MGI.
DR CDD; cd00063; FN3; 1.
DR Gene3D; 2.60.40.10; -; 4.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR013098; Ig_I-set.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR Pfam; PF00041; fn3; 1.
DR Pfam; PF07679; I-set; 1.
DR SMART; SM00060; FN3; 2.
DR SMART; SM00409; IG; 2.
DR SMART; SM00408; IGc2; 2.
DR SUPFAM; SSF48726; SSF48726; 2.
DR SUPFAM; SSF49265; SSF49265; 1.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS50835; IG_LIKE; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; Angiogenesis; Developmental protein; Differentiation;
KW Disulfide bond; Glycoprotein; Immunoglobulin domain; Phosphoprotein;
KW Receptor; Reference proteome; Repeat; Signal.
FT SIGNAL 1..27
FT /evidence="ECO:0000255"
FT CHAIN 28..1012
FT /note="Roundabout homolog 4"
FT /id="PRO_0000031041"
FT DOMAIN 32..132
FT /note="Ig-like C2-type 1"
FT DOMAIN 138..225
FT /note="Ig-like C2-type 2"
FT DOMAIN 249..346
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 348..443
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT REGION 533..553
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 586..616
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 711..801
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 980..1012
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 533..549
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 731..746
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 756..791
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 814
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8WZ75"
FT MOD_RES 947
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CARBOHYD 201
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 247
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 361
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 390
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 397
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 681
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 713
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 762
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 783
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 53..115
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 159..208
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT VAR_SEQ 440
FT /note="L -> LGEGKALSISSTPPPCRPSVSQFLSYIFSSSLSCLLVPLTVPLALPL
FT SSTSQT (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_010663"
FT VAR_SEQ 688..694
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_010662"
SQ SEQUENCE 1012 AA; 108499 MW; 9116352CAE767CC1 CRC64;
MGSGGTGLLG TEWPLPLLLL FIMGGEALDS PPQILVHPQD QLLQGSGPAK MRCRSSGQPP
PTIRWLLNGQ PLSMATPDLH YLLPDGTLLL HRPSVQGRPQ DDQNILSAIL GVYTCEASNR
LGTAVSRGAR LSVAVLQEDF QIQPRDTVAV VGESLVLECG PPWGYPKPSV SWWKDGKPLV
LQPGRRTVSG DSLMVSRAEK NDSGTYMCMA TNNAGQRESR AARVSIQESQ DHKEHLELLA
VRIQLENVTL LNPEPVKGPK PGPSVWLSWK VSGPAAPAES YTALFRTQRS PRDQGSPWTE
VLLRGLQSAK LGGLHWGQDY EFKVRPSSGR ARGPDSNVLL LRLPEQVPSA PPQGVTLRSG
NGSVFVSWAP PPAESHNGVI RGYQVWSLGN ASLPAANWTV VGEQTQLEIA TRLPGSYCVQ
VAAVTGAGAG ELSTPVCLLL EQAMEQSARD PRKHVPWTLE QLRATLRRPE VIASSAVLLW
LLLLGITVCI YRRRKAGVHL GPGLYRYTSE DAILKHRMDH SDSPWLADTW RSTSGSRDLS
SSSSLSSRLG LDPRDPLEGR RSLISWDPRS PGVPLLPDTS TFYGSLIAEQ PSSPPVRPSP
KTPAARRFPS KLAGTSSPWA SSDSLCSRRG LCSPRMSLTP TEAWKAKKKQ ELHQANSSPL
LRGSHPMEIW AWELGSRASK NLSQSPGPNS GSPGEAPRAV VSWRAVGPQL HRNSSELASR
PLPPTPLSLR GASSHDPQSQ CVEKLQAPSS DPLPAAPLSV LNSSRPSSPQ ASFLSCPSPS
SSNLSSSSLS SLEEEEDQDS VLTPEEVALC LELSDGEETP TNSVSPMPRA PSPPTTYGYI
SIPTCSGLAD MGRAGGGVGS EVGNLLYPPR PCPTPTPSEG SLANGWGSAS EDNVPSARAS
LVSSSDGSFL ADTHFARALA VAVDSFGLSL DPREADCVFT DASSPPSPRG DLSLTRSFSL
PLWEWRPDWL EDAEISHTQR LGRGLPPWPP DSRASSQRSW LTGAVPKAGD SS
