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   27-MAR-2024, entry version 160.
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=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=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.ENSMUSP00000150722; -.
DR   GlyCosmos; Q8C310; 9 sites, No reported glycans.
DR   GlyGen; Q8C310; 9 sites.
DR   iPTMnet; Q8C310; -.
DR   PhosphoSitePlus; Q8C310; -.
DR   jPOST; Q8C310; -.
DR   MaxQB; Q8C310; -.
DR   PaxDb; 10090-ENSMUSP00000099959; -.
DR   ProteomicsDB; 301637; -. [Q8C310-1]
DR   ProteomicsDB; 301638; -. [Q8C310-2]
DR   ProteomicsDB; 301639; -. [Q8C310-3]
DR   Antibodypedia; 32921; 504 antibodies from 30 providers.
DR   DNASU; 74144; -.
DR   Ensembl; ENSMUST00000102895.7; ENSMUSP00000099959.6; ENSMUSG00000032125.22. [Q8C310-2]
DR   Ensembl; ENSMUST00000214185.3; ENSMUSP00000150722.3; ENSMUSG00000032125.22. [Q8C310-1]
DR   GeneID; 74144; -.
DR   KEGG; mmu:74144; -.
DR   UCSC; uc009ous.1; mouse. [Q8C310-2]
DR   UCSC; uc012gqy.1; mouse. [Q8C310-1]
DR   AGR; MGI:1921394; -.
DR   CTD; 54538; -.
DR   MGI; MGI:1921394; Robo4.
DR   VEuPathDB; HostDB:ENSMUSG00000032125; -.
DR   eggNOG; KOG4222; Eukaryota.
DR   GeneTree; ENSGT00940000161382; -.
DR   InParanoid; Q8C310; -.
DR   OrthoDB; 5352847at2759; -.
DR   PhylomeDB; Q8C310; -.
DR   TreeFam; TF351053; -.
DR   BioGRID-ORCS; 74144; 1 hit in 76 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 166 other cell types or tissues.
DR   ExpressionAtlas; Q8C310; baseline and differential.
DR   GO; GO:0009897; C:external side of plasma membrane; IDA:MGI.
DR   GO; GO:0016020; C:membrane; TAS:MGI.
DR   GO; GO:0038023; F:signaling receptor activity; IDA:MGI.
DR   GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
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; Immunoglobulins; 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   PANTHER; PTHR44170; PROTEIN SIDEKICK; 1.
DR   PANTHER; PTHR44170:SF49; PROTEIN SIDEKICK; 1.
DR   Pfam; PF00041; fn3; 1.
DR   Pfam; PF07679; I-set; 1.
DR   Pfam; PF13927; Ig_3; 1.
DR   SMART; SM00060; FN3; 2.
DR   SMART; SM00409; IG; 2.
DR   SMART; SM00408; IGc2; 2.
DR   SUPFAM; SSF49265; Fibronectin type III; 1.
DR   SUPFAM; SSF48726; Immunoglobulin; 2.
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
//