SPY2_MOUSE
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 03-AUG-2022, entry version 159.
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 ith 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 iPTMnet; Q9QXV8; -.
DR PhosphoSitePlus; Q9QXV8; -.
DR SwissPalm; Q9QXV8; -.
DR MaxQB; Q9QXV8; -.
DR PaxDb; Q9QXV8; -.
DR PRIDE; Q9QXV8; -.
DR ProteomicsDB; 261645; -.
DR Antibodypedia; 10392; 309 antibodies from 36 providers.
DR DNASU; 24064; -.
DR Ensembl; ENSMUST00000022709; ENSMUSP00000022709; ENSMUSG00000022114.
DR GeneID; 24064; -.
DR KEGG; mmu:24064; -.
DR UCSC; uc007uxy.2; mouse.
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; VCCKVPS; -.
DR OrthoDB; 1157681at2759; -.
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 72 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 301 other tissues.
DR ExpressionAtlas; Q9QXV8; baseline and differential.
DR Genevisible; Q9QXV8; MM.
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:0019901; F:protein kinase binding; ISO:MGI.
DR GO; GO:0043539; F:protein serine/threonine kinase activator activity; ISO: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:0034260; P:negative regulation of GTPase activity; IDA:MGI.
DR GO; GO:1902747; P:negative regulation of lens fiber cell differentiation; IDA:UniProtKB.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IDA:MGI.
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: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 protein kinase B signaling; 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 InterPro; IPR030780; SPRY2.
DR PANTHER; PTHR12365:SF8; PTHR12365:SF8; 1.
DR Pfam; PF05210; Sprouty; 1.
DR PROSITE; PS51227; SPR; 1.
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
