ID   SPY2_MOUSE              Reviewed;         315 AA.
AC   Q9QXV8; Q9WUQ9;
DT   21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-MAY-2000, sequence version 1.
DT   24-JAN-2024, entry version 167.
DE   RecName: Full=Protein sprouty homolog 2;
DE            Short=Spry-2;
GN   Name=Spry2;
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], FUNCTION, AND DEVELOPMENTAL STAGE.
RX   PubMed=10498682; DOI=10.1242/dev.126.20.4465;
RA   Minowada G., Jarvis L.A., Chi C.L., Neubueser A., Sun X., Hacohen N.,
RA   Krasnow M.A., Martin G.R.;
RT   "Vertebrate sprouty genes are induced by FGF signaling and can cause
RT   chondrodysplasia when overexpressed.";
RL   Development 126:4465-4475(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, AND DEVELOPMENTAL
RP   STAGE.
RC   STRAIN=Swiss Webster;
RX   PubMed=10074434; DOI=10.1016/s0960-9822(99)80094-3;
RA   Tefft J.D., Lee M., Smith S., Leinwand M., Zhao J., Bringas P. Jr.,
RA   Crowe D.L., Warburton D.;
RT   "Conserved function of mSpry-2, a murine homolog of Drosophila sprouty,
RT   which negatively modulates respiratory organogenesis.";
RL   Curr. Biol. 9:219-222(1999).
RN   [3]
RP   SUBUNIT, AND INTERACTION WITH CAV1 AND SPRY1.
RX   PubMed=16877379; DOI=10.1074/jbc.m603921200;
RA   Cabrita M.A., Jaeggi F., Widjaja S.P., Christofori G.;
RT   "A functional interaction between sprouty proteins and caveolin-1.";
RL   J. Biol. Chem. 281:29201-29212(2006).
RN   [4]
RP   INTERACTION WITH TESK1, AND TISSUE SPECIFICITY.
RX   PubMed=17974561; DOI=10.1074/jbc.m705457200;
RA   Chandramouli S., Yu C.Y., Yusoff P., Lao D.H., Leong H.F., Mizuno K.,
RA   Guy G.R.;
RT   "Tesk1 interacts with Spry2 to abrogate its inhibition of ERK
RT   phosphorylation downstream of receptor tyrosine kinase signaling.";
RL   J. Biol. Chem. 283:1679-1691(2008).
RN   [5]
RP   FUNCTION.
RX   PubMed=25576668; DOI=10.1016/j.exer.2015.01.001;
RA   Zhao G., Wojciechowski M.C., Jee S., Boros J., McAvoy J.W., Lovicu F.J.;
RT   "Negative regulation of TGFbeta-induced lens epithelial to mesenchymal
RT   transition (EMT) by RTK antagonists.";
RL   Exp. Eye Res. 132:9-16(2015).
RN   [6]
RP   FUNCTION, AND MUTAGENESIS OF TYR-55.
RX   PubMed=29501879; DOI=10.1016/j.exer.2018.02.025;
RA   Zhao G., Bailey C.G., Feng Y., Rasko J., Lovicu F.J.;
RT   "Negative regulation of lens fiber cell differentiation by RTK antagonists
RT   Spry and Spred.";
RL   Exp. Eye Res. 170:148-159(2018).
CC   -!- FUNCTION: Antagonist of fibroblast growth factor (FGF) pathways via
CC       inhibition of FGF-mediated phosphorylation of ERK1/2 (PubMed:29501879).
CC       Thereby acts as an antagonist of FGF-induced retinal lens fiber
CC       differentiation, may inhibit limb bud outgrowth and may negatively
CC       modulate respiratory organogenesis (PubMed:10498682, PubMed:10074434,
CC       PubMed:29501879). Inhibits TGFB-induced epithelial-to-mesenchymal
CC       transition in retinal lens epithelial cells (PubMed:25576668). Inhibits
CC       CBL/C-CBL-mediated EGFR ubiquitination (By similarity).
CC       {ECO:0000250|UniProtKB:O43597, ECO:0000269|PubMed:10074434,
CC       ECO:0000269|PubMed:10498682, ECO:0000269|PubMed:25576668,
CC       ECO:0000269|PubMed:29501879}.
CC   -!- SUBUNIT: Forms heterodimers with SPRY1 (PubMed:16877379). Forms a
CC       tripartite complex containing GAB1, METTL13 and SPRY2 (By similarity).
CC       Within the complex interacts with METTL13 (By similarity). Interacts
CC       with RAF1 (By similarity). Interacts (via C-terminus) with TESK1 (via
CC       C-terminus); the interaction disrupts SPRY2 interaction with GRB2,
CC       potentially via disruption of SPRY2 serine dephosphorylation
CC       (PubMed:17974561). Interacts with PPP2R1A/PP2A-A and PPP2CA/PP2A-C; the
CC       interaction with PPP2CA/PP2A-C is inhibited by interaction with TESK1,
CC       possibly by vesicular sequestration of SPRY2 (By similarity).
CC       Inhibition of the interaction with the serine/threonine-protein
CC       phosphatase 2A (PP2A) holoenzyme results in loss of PP2A-mediated
CC       dephosphorylation, resulting in the loss of SPRY2 interaction with GRB2
CC       (By similarity). Interacts with GRB2 (By similarity). Interacts with
CC       CBL/C-CBL; the interaction inhibits CBL-mediated ubiquitination of EGFR
CC       (By similarity). Interacts (via C-terminus) with CAV1 (via C-terminus)
CC       (PubMed:16877379). {ECO:0000250|UniProtKB:O43597,
CC       ECO:0000269|PubMed:16877379, ECO:0000269|PubMed:17974561}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton
CC       {ECO:0000250|UniProtKB:O43597}. Cell projection, ruffle membrane
CC       {ECO:0000250|UniProtKB:O43597}. Note=Associated with microtubules in
CC       unstimulated cells but is translocated to the membrane ruffles in cells
CC       stimulated with EGF (epidermal growth factor).
CC       {ECO:0000250|UniProtKB:O43597}.
CC   -!- TISSUE SPECIFICITY: Expressed in the testes and brain (at protein
CC       level) (PubMed:17974561, PubMed:10074434). In adult, highly expressed
CC       in the lung, heart and at lower levels in skeletal muscle and kidney
CC       (PubMed:10074434). {ECO:0000269|PubMed:10074434,
CC       ECO:0000269|PubMed:17974561}.
CC   -!- DEVELOPMENTAL STAGE: At 8.5 dpc, expressed in the primitive streak,
CC       rostral forebrain, cells lateral to the posterior hindbrain, anterior
CC       hindbrain and developing midbrain. At 9.5 dpc, continues to be
CC       expressed in the rostral forebrain and primitive streak, and is also
CC       detected in the branchial arches and the forelimb bud. At 10.5 dpc,
CC       expressed in the somites, frontonasal processes, tailbud, and hindlimb
CC       bud (PubMed:10498682). Highly expressed in lung epithelial cells,
CC       primarily in the distal airways at 12 dpc (PubMed:10074434).
CC       {ECO:0000269|PubMed:10074434, ECO:0000269|PubMed:10498682}.
CC   -!- DOMAIN: The Cys-rich domain is responsible for the localization of the
CC       protein to the membrane ruffles.
CC   -!- PTM: Cleaved at Pro-143 by the prolyl endopeptidase FAP (seprase)
CC       activity (in vitro). {ECO:0000250|UniProtKB:O43597}.
CC   -!- SIMILARITY: Belongs to the sprouty family. {ECO:0000305}.
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DR   EMBL; AF176905; AAD56006.1; -; mRNA.
DR   EMBL; AF153084; AAD34167.1; -; mRNA.
DR   CCDS; CCDS27321.1; -.
DR   RefSeq; NP_036027.1; NM_011897.3.
DR   RefSeq; XP_006519079.1; XM_006519016.3.
DR   AlphaFoldDB; Q9QXV8; -.
DR   SMR; Q9QXV8; -.
DR   BioGRID; 204877; 14.
DR   IntAct; Q9QXV8; 1.
DR   STRING; 10090.ENSMUSP00000022709; -.
DR   GlyGen; Q9QXV8; 3 sites, 1 O-linked glycan (3 sites).
DR   iPTMnet; Q9QXV8; -.
DR   PhosphoSitePlus; Q9QXV8; -.
DR   SwissPalm; Q9QXV8; -.
DR   MaxQB; Q9QXV8; -.
DR   PaxDb; 10090-ENSMUSP00000022709; -.
DR   ProteomicsDB; 261645; -.
DR   Pumba; Q9QXV8; -.
DR   Antibodypedia; 10392; 344 antibodies from 36 providers.
DR   DNASU; 24064; -.
DR   Ensembl; ENSMUST00000022709.6; ENSMUSP00000022709.5; ENSMUSG00000022114.6.
DR   GeneID; 24064; -.
DR   KEGG; mmu:24064; -.
DR   UCSC; uc007uxy.2; mouse.
DR   AGR; MGI:1345138; -.
DR   CTD; 10253; -.
DR   MGI; MGI:1345138; Spry2.
DR   VEuPathDB; HostDB:ENSMUSG00000022114; -.
DR   eggNOG; ENOG502QTG8; Eukaryota.
DR   GeneTree; ENSGT00950000183055; -.
DR   HOGENOM; CLU_077696_0_0_1; -.
DR   InParanoid; Q9QXV8; -.
DR   OMA; MHAYRCE; -.
DR   OrthoDB; 4219076at2759; -.
DR   PhylomeDB; Q9QXV8; -.
DR   TreeFam; TF325070; -.
DR   Reactome; R-MMU-1295596; Spry regulation of FGF signaling.
DR   Reactome; R-MMU-182971; EGFR downregulation.
DR   BioGRID-ORCS; 24064; 3 hits in 77 CRISPR screens.
DR   ChiTaRS; Spry2; mouse.
DR   PRO; PR:Q9QXV8; -.
DR   Proteomes; UP000000589; Chromosome 14.
DR   RNAct; Q9QXV8; Protein.
DR   Bgee; ENSMUSG00000022114; Expressed in lung epithelium and 303 other cell types or tissues.
DR   ExpressionAtlas; Q9QXV8; baseline and differential.
DR   GO; GO:0015629; C:actin cytoskeleton; ISO:MGI.
DR   GO; GO:0005856; C:cytoskeleton; IDA:BHF-UCL.
DR   GO; GO:0005829; C:cytosol; IDA:BHF-UCL.
DR   GO; GO:0016020; C:membrane; IDA:BHF-UCL.
DR   GO; GO:0015630; C:microtubule cytoskeleton; ISO:MGI.
DR   GO; GO:1990752; C:microtubule end; ISO:MGI.
DR   GO; GO:0005634; C:nucleus; IDA:BHF-UCL.
DR   GO; GO:0032587; C:ruffle membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0140678; F:molecular function inhibitor activity; IMP:MGI.
DR   GO; GO:0019901; F:protein kinase binding; ISO:MGI.
DR   GO; GO:0043539; F:protein serine/threonine kinase activator activity; ISO:MGI.
DR   GO; GO:0055105; F:ubiquitin-protein transferase inhibitor activity; IMP:MGI.
DR   GO; GO:0048513; P:animal organ development; IBA:GO_Central.
DR   GO; GO:0048754; P:branching morphogenesis of an epithelial tube; IMP:MGI.
DR   GO; GO:0060449; P:bud elongation involved in lung branching; IGI:MGI.
DR   GO; GO:0045165; P:cell fate commitment; IMP:MGI.
DR   GO; GO:1990830; P:cellular response to leukemia inhibitory factor; IEP:MGI.
DR   GO; GO:0035924; P:cellular response to vascular endothelial growth factor stimulus; ISO:MGI.
DR   GO; GO:0070371; P:ERK1 and ERK2 cascade; IGI:MGI.
DR   GO; GO:0000132; P:establishment of mitotic spindle orientation; IGI:MGI.
DR   GO; GO:0008543; P:fibroblast growth factor receptor signaling pathway; IGI:MGI.
DR   GO; GO:0042472; P:inner ear morphogenesis; IMP:MGI.
DR   GO; GO:0030324; P:lung development; IMP:MGI.
DR   GO; GO:0060437; P:lung growth; IDA:MGI.
DR   GO; GO:0060425; P:lung morphogenesis; IDA:MGI.
DR   GO; GO:0016525; P:negative regulation of angiogenesis; ISO:MGI.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:MGI.
DR   GO; GO:0031345; P:negative regulation of cell projection organization; IDA: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:0040037; P:negative regulation of fibroblast growth factor receptor signaling pathway; IDA:MGI.
DR   GO; GO:1902747; P:negative regulation of lens fiber cell differentiation; IDA:UniProtKB.
DR   GO; GO:0051387; P:negative regulation of neurotrophin TRK receptor signaling pathway; IDA:MGI.
DR   GO; GO:0010801; P:negative regulation of peptidyl-threonine phosphorylation; ISO:MGI.
DR   GO; GO:0031397; P:negative regulation of protein ubiquitination; ISS:UniProtKB.
DR   GO; GO:0046580; P:negative regulation of Ras protein signal transduction; IDA:MGI.
DR   GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; IDA:UniProtKB.
DR   GO; GO:1900747; P:negative regulation of vascular endothelial growth factor signaling pathway; ISO:MGI.
DR   GO; GO:0030335; P:positive regulation of cell migration; ISO:MGI.
DR   GO; GO:0045742; P:positive regulation of epidermal growth factor receptor signaling pathway; IMP:MGI.
DR   GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISO:MGI.
DR   GO; GO:0010628; P:positive regulation of gene expression; ISO:MGI.
DR   GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; ISO:MGI.
DR   GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISO:MGI.
DR   GO; GO:0060541; P:respiratory system development; IDA:MGI.
DR   GO; GO:0007605; P:sensory perception of sound; IMP:MGI.
DR   InterPro; IPR007875; Sprouty.
DR   PANTHER; PTHR12365:SF8; PROTEIN SPROUTY HOMOLOG 2; 1.
DR   PANTHER; PTHR12365; SPROUTY; 1.
DR   Pfam; PF05210; Sprouty; 1.
DR   PROSITE; PS51227; SPR; 1.
DR   Genevisible; Q9QXV8; MM.
PE   1: Evidence at protein level;
KW   Cell membrane; Cell projection; Cytoplasm; Cytoskeleton;
KW   Developmental protein; Membrane; Microtubule; Reference proteome.
FT   CHAIN           1..315
FT                   /note="Protein sprouty homolog 2"
FT                   /id="PRO_0000076902"
FT   DOMAIN          177..291
FT                   /note="SPR"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00572"
FT   REGION          1..39
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          51..141
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          117..315
FT                   /note="Required for interaction with CAV1"
FT                   /evidence="ECO:0000269|PubMed:16877379"
FT   REGION          178..315
FT                   /note="Required for interaction with TESK1"
FT                   /evidence="ECO:0000250|UniProtKB:O43597"
FT   COMPBIAS        1..19
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        73..88
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        94..136
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            143..144
FT                   /note="Cleavage; by FAP"
FT                   /evidence="ECO:0000250|UniProtKB:O43597"
FT   MUTAGEN         55
FT                   /note="Y->A: Abolishes FGF2-induced lens fiber
FT                   differentiation via inhibition of FGF-mediated ERK1/2
FT                   phosphorylation."
FT                   /evidence="ECO:0000269|PubMed:29501879"
FT   CONFLICT        163
FT                   /note="V -> I (in Ref. 2; AAD34167)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   315 AA;  34623 MW;  81514698EAD809A7 CRC64;
     MEARAQSGNG SQPLLQTAHD SGRQRGEPDP RDALTQQVHV LSLDQIRAIR NTNEYTEGPT
     VVPRPGLKPA PRPSTQHKHE RLHGLPEHRQ PPRLQPSQVH SSRAPLSRSI STVSSGSRSS
     TRTSTSSSSS EQRLLGPSFS HGPAAADGII RVQPKSELKP GDVKPLSKDD LGLHAYRCED
     CGKCKCKECT YPRPLPSDWI CDKQCLCSAQ NVIDYGTCVC CVKGLFYHCS NDDEDNCADN
     PCSCSQSHCC TRWSAMGVMS LFLPCLWCYL PAKGCLKLCQ GCYDRVNRPG CRCKNSNTVC
     CKVPTVPPRN FEKPT
//