ID SPRE2_HUMAN Reviewed; 418 AA. AC Q7Z698; A1L3V4; B7Z5K7; D6W5F7; E9PEP0; Q2NKX6; DT 04-JAN-2005, integrated into UniProtKB/Swiss-Prot. DT 25-JUL-2006, sequence version 2. DT 24-JAN-2024, entry version 168. DE RecName: Full=Sprouty-related, EVH1 domain-containing protein 2; DE Short=Spred-2; GN Name=SPRED2; 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 1), FUNCTION, SUBUNIT, INTERACTION WITH RP SPRED1, AND PHOSPHORYLATION. RC TISSUE=Glioblastoma; RX PubMed=15683364; DOI=10.1042/bj20041284; RA King J.A.J., Straffon A.F.L., D'Abaco G.M., Poon C.L.C., I S.T.T., RA Smith C.M., Buchert M., Corcoran N.M., Hall N.E., Callus B.A., Sarcevic B., RA Martin D., Lock P., Hovens C.M.; RT "Distinct requirements for the Sprouty domain for functional activity of RT Spred proteins."; RL Biochem. J. 388:445-454(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [4] 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, and Ovary; 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 [6] RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=15580519; DOI=10.1007/s00418-004-0725-6; RA Engelhardt C.M., Bundschu K., Messerschmitt M., Renne T., Walter U., RA Reinhard M., Schuh K.; RT "Expression and subcellular localization of Spred proteins in mouse and RT human tissues."; RL Histochem. Cell Biol. 122:527-538(2004). RN [7] RP UBIQUITINATION, PHOSPHORYLATION AT TYR-228 AND TYR-231, AND MUTAGENESIS OF RP TYR-228; TYR-231; TYR-240; TYR-251; TYR-264; TYR-266; TYR-268; TYR-311; RP TYR-351 AND TYR-394. RX PubMed=17094949; DOI=10.1016/j.bbrc.2006.10.150; RA Lock P., I S.T.T., Straffon A.F., Schieb H., Hovens C.M., Stylli S.S.; RT "Spred-2 steady-state levels are regulated by phosphorylation and Cbl- RT mediated ubiquitination."; RL Biochem. Biophys. Res. Commun. 351:1018-1023(2006). RN [8] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-206, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; 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). RN [9] RP STRUCTURE BY NMR OF 1-124. RX PubMed=15213456; DOI=10.1023/b:jnmr.0000032526.17586.8c; RA Zimmermann J., Jarchau T., Walter U., Oschkinat H., Ball L.J.; RT "1H, 13C and 15N resonance assignment of the human Spred2 EVH1 domain."; RL J. Biomol. NMR 29:435-436(2004). RN [10] RP VARIANTS NS14 63-ARG--ALA-418 DEL AND PRO-100, CHARACTERIZATION OF VARIANTS RP NS14 63-ARG--ALA-418 DEL AND PRO-100, INVOLVEMENT IN NS14, SUBCELLULAR RP LOCATION, INTERACTION WITH NF1, AND FUNCTION. RX PubMed=34626534; DOI=10.1016/j.ajhg.2021.09.007; RA Motta M., Fasano G., Gredy S., Brinkmann J., Bonnard A.A., RA Simsek-Kiper P.O., Gulec E.Y., Essaddam L., Utine G.E., RA Guarnetti Prandi I., Venditti M., Pantaleoni F., Radio F.C., Ciolfi A., RA Petrini S., Consoli F., Vignal C., Hepbasli D., Ullrich M., de Boer E., RA Vissers L.E.L.M., Gritli S., Rossi C., De Luca A., Ben Becher S., RA Gelb B.D., Dallapiccola B., Lauri A., Chillemi G., Schuh K., Cave H., RA Zenker M., Tartaglia M.; RT "SPRED2 loss-of-function causes a recessive Noonan syndrome-like RT phenotype."; RL Am. J. Hum. Genet. 108:2112-2129(2021). CC -!- FUNCTION: Negatively regulates Ras signaling pathways and downstream CC activation of MAP kinases (PubMed:15683364, PubMed:34626534). Recruits CC and translocates NF1 to the cell membrane, thereby enabling NF1- CC dependent hydrolysis of active GTP-bound Ras to inactive GDP-bound Ras CC (PubMed:34626534). Inhibits fibroblast growth factor (FGF)-induced CC retinal lens fiber differentiation, probably by inhibiting FGF-mediated CC phosphorylation of ERK1/2 (By similarity). Inhibits TGFB-induced CC epithelial-to-mesenchymal transition in lens epithelial cells (By CC similarity). {ECO:0000250|UniProtKB:Q924S7, CC ECO:0000269|PubMed:15683364, ECO:0000269|PubMed:34626534}. CC -!- SUBUNIT: Homodimer and heterodimer (PubMed:15683364). Able to interact CC with SPRED1 to form heterodimers (PubMed:15683364). Interacts with RAS CC (By similarity). May interact with ZDHHC13 (via ANK repeats) and CC ZDHHC17 (via ANK repeats) (By similarity). Interacts with TESK1 (By CC similarity). Interacts with NF1 (PubMed:34626534). CC {ECO:0000250|UniProtKB:Q924S7, ECO:0000269|PubMed:15683364, CC ECO:0000269|PubMed:34626534}. CC -!- INTERACTION: CC Q7Z698; Q92870-2: APBB2; NbExp=3; IntAct=EBI-7082156, EBI-21535880; CC Q7Z698; P29972: AQP1; NbExp=3; IntAct=EBI-7082156, EBI-745213; CC Q7Z698; P27797: CALR; NbExp=3; IntAct=EBI-7082156, EBI-1049597; CC Q7Z698; P28329-3: CHAT; NbExp=3; IntAct=EBI-7082156, EBI-25837549; CC Q7Z698; P36957: DLST; NbExp=3; IntAct=EBI-7082156, EBI-351007; CC Q7Z698; G5E9A7: DMWD; NbExp=3; IntAct=EBI-7082156, EBI-10976677; CC Q7Z698; P50570-2: DNM2; NbExp=3; IntAct=EBI-7082156, EBI-10968534; CC Q7Z698; P22607: FGFR3; NbExp=3; IntAct=EBI-7082156, EBI-348399; CC Q7Z698; P14136: GFAP; NbExp=3; IntAct=EBI-7082156, EBI-744302; CC Q7Z698; Q53GS7: GLE1; NbExp=3; IntAct=EBI-7082156, EBI-1955541; CC Q7Z698; P28799: GRN; NbExp=3; IntAct=EBI-7082156, EBI-747754; CC Q7Z698; A0A024R8L2: hCG_1987119; NbExp=3; IntAct=EBI-7082156, EBI-14103818; CC Q7Z698; P42858: HTT; NbExp=6; IntAct=EBI-7082156, EBI-466029; CC Q7Z698; Q9NZI2-2: KCNIP1; NbExp=3; IntAct=EBI-7082156, EBI-22452746; CC Q7Z698; O60333-2: KIF1B; NbExp=3; IntAct=EBI-7082156, EBI-10975473; CC Q7Z698; Q5T749: KPRP; NbExp=3; IntAct=EBI-7082156, EBI-10981970; CC Q7Z698; P59991: KRTAP12-2; NbExp=3; IntAct=EBI-7082156, EBI-10176379; CC Q7Z698; Q9BYR9: KRTAP2-4; NbExp=3; IntAct=EBI-7082156, EBI-14065470; CC Q7Z698; Q5T751: LCE1C; NbExp=3; IntAct=EBI-7082156, EBI-12224199; CC Q7Z698; O14633: LCE2B; NbExp=3; IntAct=EBI-7082156, EBI-11478468; CC Q7Z698; Q5TCM9: LCE5A; NbExp=3; IntAct=EBI-7082156, EBI-11955689; CC Q7Z698; P02545: LMNA; NbExp=3; IntAct=EBI-7082156, EBI-351935; CC Q7Z698; Q99750: MDFI; NbExp=3; IntAct=EBI-7082156, EBI-724076; CC Q7Z698; P62166: NCS1; NbExp=3; IntAct=EBI-7082156, EBI-746987; CC Q7Z698; P17568: NDUFB7; NbExp=3; IntAct=EBI-7082156, EBI-1246238; CC Q7Z698; P19404: NDUFV2; NbExp=3; IntAct=EBI-7082156, EBI-713665; CC Q7Z698; Q8TDX7: NEK7; NbExp=3; IntAct=EBI-7082156, EBI-1055945; CC Q7Z698; P29474: NOS3; NbExp=3; IntAct=EBI-7082156, EBI-1391623; CC Q7Z698; D3DTS7: PMP22; NbExp=3; IntAct=EBI-7082156, EBI-25882629; CC Q7Z698; P60891: PRPS1; NbExp=3; IntAct=EBI-7082156, EBI-749195; CC Q7Z698; P47897: QARS1; NbExp=3; IntAct=EBI-7082156, EBI-347462; CC Q7Z698; Q5RL73: RBM48; NbExp=3; IntAct=EBI-7082156, EBI-473821; CC Q7Z698; Q9Y3C5: RNF11; NbExp=3; IntAct=EBI-7082156, EBI-396669; CC Q7Z698; P51812: RPS6KA3; NbExp=4; IntAct=EBI-7082156, EBI-1046616; CC Q7Z698; Q9UK32: RPS6KA6; NbExp=3; IntAct=EBI-7082156, EBI-722467; CC Q7Z698; Q9NZD8: SPG21; NbExp=10; IntAct=EBI-7082156, EBI-742688; CC Q7Z698; Q7Z699: SPRED1; NbExp=3; IntAct=EBI-7082156, EBI-5235340; CC Q7Z698; O95985: TOP3B; NbExp=4; IntAct=EBI-7082156, EBI-373403; CC Q7Z698; Q99598: TSNAX; NbExp=3; IntAct=EBI-7082156, EBI-742638; CC Q7Z698; P62760: VSNL1; NbExp=3; IntAct=EBI-7082156, EBI-740943; CC Q7Z698; O76024: WFS1; NbExp=3; IntAct=EBI-7082156, EBI-720609; CC Q7Z698; Q8IUH5: ZDHHC17; NbExp=3; IntAct=EBI-7082156, EBI-524753; CC Q7Z698; P15622-3: ZNF250; NbExp=3; IntAct=EBI-7082156, EBI-10177272; CC Q7Z698; Q96IQ9: ZNF414; NbExp=3; IntAct=EBI-7082156, EBI-744257; CC Q7Z698; Q8TAU3: ZNF417; NbExp=3; IntAct=EBI-7082156, EBI-740727; CC Q7Z698; Q86XF7: ZNF575; NbExp=3; IntAct=EBI-7082156, EBI-14069183; CC Q7Z698; Q96EG3: ZNF837; NbExp=6; IntAct=EBI-7082156, EBI-11962574; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:34626534}; CC Peripheral membrane protein {ECO:0000250|UniProtKB:Q924S7}; Cytoplasmic CC side {ECO:0000250|UniProtKB:Q924S7}. Cytoplasmic vesicle, secretory CC vesicle membrane {ECO:0000269|PubMed:15580519}; Peripheral membrane CC protein {ECO:0000305}; Cytoplasmic side {ECO:0000305}. Cytoplasm CC {ECO:0000269|PubMed:15580519}. Note=Detected in the cytoplasm of the CC stratum spinosum cells, where it is associated with cytoplasmic CC vesicles that are supposed to be secretory granules. CC {ECO:0000269|PubMed:15580519}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q7Z698-1; Sequence=Displayed; CC Name=2; CC IsoId=Q7Z698-2; Sequence=VSP_043755; CC -!- TISSUE SPECIFICITY: Expressed in liver, skin, small intestine, salivary CC gland and prostate. {ECO:0000269|PubMed:15580519}. CC -!- PTM: Phosphorylated on serine and threonine residues (PubMed:15683364). CC Phosphorylated on tyrosine. Phosphorylation of Tyr-228 and Tyr-231 are CC required for ubiquitination (PubMed:17094949). CC {ECO:0000269|PubMed:15683364, ECO:0000269|PubMed:17094949}. CC -!- PTM: Ubiquitinated; leading to degradation by the proteasome. CC {ECO:0000269|PubMed:17094949}. CC -!- DISEASE: Noonan syndrome 14 (NS14) [MIM:619745]: A form of Noonan CC syndrome, a disease characterized by short stature, facial dysmorphic CC features such as hypertelorism, a downward eyeslant and low-set CC posteriorly rotated ears, and a high incidence of congenital heart CC defects and hypertrophic cardiomyopathy. Other features can include a CC short neck with webbing or redundancy of skin, deafness, motor delay, CC variable intellectual deficits, multiple skeletal defects, CC cryptorchidism, and bleeding diathesis. NS14 inheritance is autosomal CC recessive. {ECO:0000269|PubMed:34626534}. Note=The disease is caused by CC variants affecting the gene represented in this entry. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY299090; AAP59415.1; -; mRNA. DR EMBL; AK299079; BAH12943.1; -; mRNA. DR EMBL; AC012370; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC097503; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471053; EAW99905.1; -; Genomic_DNA. DR EMBL; CH471053; EAW99906.1; -; Genomic_DNA. DR EMBL; BC111495; AAI11496.1; -; mRNA. DR EMBL; BC130292; AAI30293.1; -; mRNA. DR EMBL; BC136334; AAI36335.1; -; mRNA. DR CCDS; CCDS33211.1; -. [Q7Z698-1] DR CCDS; CCDS46308.1; -. [Q7Z698-2] DR RefSeq; NP_001121682.1; NM_001128210.1. [Q7Z698-2] DR RefSeq; NP_861449.2; NM_181784.2. [Q7Z698-1] DR PDB; 2JP2; NMR; -; A=1-124. DR PDB; 8EQ5; X-ray; 1.80 A; B=131-160. DR PDBsum; 2JP2; -. DR PDBsum; 8EQ5; -. DR AlphaFoldDB; Q7Z698; -. DR BMRB; Q7Z698; -. DR SMR; Q7Z698; -. DR BioGRID; 128344; 61. DR IntAct; Q7Z698; 58. DR MINT; Q7Z698; -. DR STRING; 9606.ENSP00000348753; -. DR iPTMnet; Q7Z698; -. DR PhosphoSitePlus; Q7Z698; -. DR SwissPalm; Q7Z698; -. DR BioMuta; SPRED2; -. DR DMDM; 110825745; -. DR EPD; Q7Z698; -. DR jPOST; Q7Z698; -. DR MassIVE; Q7Z698; -. DR MaxQB; Q7Z698; -. DR PaxDb; 9606-ENSP00000348753; -. DR PeptideAtlas; Q7Z698; -. DR ProteomicsDB; 69384; -. [Q7Z698-1] DR ProteomicsDB; 69385; -. [Q7Z698-2] DR Pumba; Q7Z698; -. DR Antibodypedia; 30873; 163 antibodies from 30 providers. DR DNASU; 200734; -. DR Ensembl; ENST00000356388.9; ENSP00000348753.4; ENSG00000198369.10. [Q7Z698-1] DR Ensembl; ENST00000443619.6; ENSP00000393697.2; ENSG00000198369.10. [Q7Z698-2] DR GeneID; 200734; -. DR KEGG; hsa:200734; -. DR MANE-Select; ENST00000356388.9; ENSP00000348753.4; NM_181784.3; NP_861449.2. DR UCSC; uc002sdr.5; human. [Q7Z698-1] DR AGR; HGNC:17722; -. DR CTD; 200734; -. DR DisGeNET; 200734; -. DR GeneCards; SPRED2; -. DR HGNC; HGNC:17722; SPRED2. DR HPA; ENSG00000198369; Low tissue specificity. DR MalaCards; SPRED2; -. DR MIM; 609292; gene. DR MIM; 619745; phenotype. DR neXtProt; NX_Q7Z698; -. DR OpenTargets; ENSG00000198369; -. DR Orphanet; 648; Noonan syndrome. DR PharmGKB; PA134956365; -. DR VEuPathDB; HostDB:ENSG00000198369; -. DR eggNOG; KOG4590; Eukaryota. DR GeneTree; ENSGT00940000156841; -. DR HOGENOM; CLU_038867_1_1_1; -. DR InParanoid; Q7Z698; -. DR OMA; CEYAPDT; -. DR OrthoDB; 3031266at2759; -. DR PhylomeDB; Q7Z698; -. DR TreeFam; TF321411; -. DR PathwayCommons; Q7Z698; -. DR Reactome; R-HSA-5658442; Regulation of RAS by GAPs. DR Reactome; R-HSA-5658623; FGFRL1 modulation of FGFR1 signaling. DR Reactome; R-HSA-6802953; RAS signaling downstream of NF1 loss-of-function variants. DR SignaLink; Q7Z698; -. DR BioGRID-ORCS; 200734; 34 hits in 1170 CRISPR screens. DR ChiTaRS; SPRED2; human. DR EvolutionaryTrace; Q7Z698; -. DR GeneWiki; SPRED2; -. DR GenomeRNAi; 200734; -. DR Pharos; Q7Z698; Tbio. DR PRO; PR:Q7Z698; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q7Z698; Protein. DR Bgee; ENSG00000198369; Expressed in sural nerve and 181 other cell types or tissues. DR ExpressionAtlas; Q7Z698; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0030658; C:transport vesicle membrane; IEA:UniProtKB-SubCell. DR GO; GO:0019901; F:protein kinase binding; IPI:BHF-UCL. DR GO; GO:0030291; F:protein serine/threonine kinase inhibitor activity; ISS:BHF-UCL. DR GO; GO:0005173; F:stem cell factor receptor binding; ISS:UniProtKB. DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; ISS:UniProtKB. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISS:UniProtKB. DR GO; GO:1902747; P:negative regulation of lens fiber cell differentiation; ISS:UniProtKB. DR GO; GO:0043409; P:negative regulation of MAPK cascade; ISS:UniProtKB. DR GO; GO:0010801; P:negative regulation of peptidyl-threonine phosphorylation; IMP:BHF-UCL. DR GO; GO:0030512; P:negative regulation of transforming growth factor beta receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0043517; P:positive regulation of DNA damage response, signal transduction by p53 class mediator; ISS:BHF-UCL. DR GO; GO:0090311; P:regulation of protein deacetylation; ISS:BHF-UCL. DR CDD; cd10574; EVH1_SPRED-like; 1. DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 1. DR InterPro; IPR023337; KBD. DR InterPro; IPR011993; PH-like_dom_sf. DR InterPro; IPR041937; SPRE_EVH1. DR InterPro; IPR007875; Sprouty. DR InterPro; IPR000697; WH1/EVH1_dom. DR PANTHER; PTHR11202:SF11; SPROUTY-RELATED, EVH1 DOMAIN-CONTAINING PROTEIN 2; 1. DR PANTHER; PTHR11202; SPROUTY-RELATED, EVH1 DOMAIN-CONTAINING PROTEIN FAMILY MEMBER; 1. DR Pfam; PF05210; Sprouty; 1. DR Pfam; PF00568; WH1; 1. DR SMART; SM00461; WH1; 1. DR SUPFAM; SSF50729; PH domain-like; 1. DR PROSITE; PS51488; KBD; 1. DR PROSITE; PS51227; SPR; 1. DR PROSITE; PS50229; WH1; 1. DR Genevisible; Q7Z698; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cytoplasm; KW Cytoplasmic vesicle; Disease variant; Membrane; Phosphoprotein; KW Reference proteome; Ubl conjugation. FT CHAIN 1..418 FT /note="Sprouty-related, EVH1 domain-containing protein 2" FT /id="PRO_0000076910" FT DOMAIN 5..122 FT /note="WH1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00410" FT DOMAIN 201..257 FT /note="KBD" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00821" FT DOMAIN 308..416 FT /note="SPR" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00572" FT REGION 127..171 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 275..302 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 145..171 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 206 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 228 FT /note="Phosphotyrosine" FT /evidence="ECO:0000305|PubMed:17094949" FT MOD_RES 231 FT /note="Phosphotyrosine" FT /evidence="ECO:0000305|PubMed:17094949" FT VAR_SEQ 1..9 FT /note="MTEETHPDD -> MASPGS (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_043755" FT VARIANT 63..418 FT /note="Missing (in NS14; results in loss of MAPK FT down-regulation; increased protein degradation)" FT /evidence="ECO:0000269|PubMed:34626534" FT /id="VAR_086929" FT VARIANT 100 FT /note="L -> P (in NS14; results in loss of MAPK FT down-regulation; increased protein degradation; properly FT targeted to the cell membrane; loss of interaction with FT NF1)" FT /evidence="ECO:0000269|PubMed:34626534" FT /id="VAR_086930" FT MUTAGEN 228 FT /note="Y->F: Reduces ubiquitination and CBL-induced FT phosphorylation; when associated with F-231." FT /evidence="ECO:0000269|PubMed:17094949" FT MUTAGEN 231 FT /note="Y->F: Reduces ubiquitination and CBL-induced FT phosphorylation; when associated with F-228." FT /evidence="ECO:0000269|PubMed:17094949" FT MUTAGEN 240 FT /note="Y->F: No effect on phosphorylation or FT ubiquitination." FT /evidence="ECO:0000269|PubMed:17094949" FT MUTAGEN 251 FT /note="Y->F: No effect on phosphorylation or FT ubiquitination." FT /evidence="ECO:0000269|PubMed:17094949" FT MUTAGEN 264 FT /note="Y->F: No effect on phosphorylation or FT ubiquitination; when associated with F-266." FT /evidence="ECO:0000269|PubMed:17094949" FT MUTAGEN 266 FT /note="Y->F: No effect on phosphorylation or FT ubiquitination; when associated with F-264." FT /evidence="ECO:0000269|PubMed:17094949" FT MUTAGEN 268 FT /note="Y->F: No effect on phosphorylation or FT ubiquitination." FT /evidence="ECO:0000269|PubMed:17094949" FT MUTAGEN 311 FT /note="Y->F: No effect on phosphorylation or FT ubiquitination." FT /evidence="ECO:0000269|PubMed:17094949" FT MUTAGEN 351 FT /note="Y->F: No effect on phosphorylation or FT ubiquitination." FT /evidence="ECO:0000269|PubMed:17094949" FT MUTAGEN 394 FT /note="Y->F: No effect on phosphorylation or FT ubiquitination." FT /evidence="ECO:0000269|PubMed:17094949" FT CONFLICT 33 FT /note="Q -> R (in Ref. 2; BAH12943)" FT /evidence="ECO:0000305" FT CONFLICT 202 FT /note="Y -> C (in Ref. 1; AAP59415)" FT /evidence="ECO:0000305" FT STRAND 5..8 FT /evidence="ECO:0007829|PDB:2JP2" FT STRAND 11..23 FT /evidence="ECO:0007829|PDB:2JP2" FT STRAND 27..32 FT /evidence="ECO:0007829|PDB:2JP2" FT STRAND 39..44 FT /evidence="ECO:0007829|PDB:2JP2" FT STRAND 57..67 FT /evidence="ECO:0007829|PDB:2JP2" FT STRAND 69..77 FT /evidence="ECO:0007829|PDB:2JP2" FT STRAND 81..85 FT /evidence="ECO:0007829|PDB:2JP2" FT STRAND 88..92 FT /evidence="ECO:0007829|PDB:2JP2" FT STRAND 94..104 FT /evidence="ECO:0007829|PDB:2JP2" FT HELIX 105..123 FT /evidence="ECO:0007829|PDB:2JP2" SQ SEQUENCE 418 AA; 47558 MW; CA4FE80C45008851 CRC64; MTEETHPDDD SYIVRVKAVV MTRDDSSGGW FPQEGGGISR VGVCKVMHPE GNGRSGFLIH GERQKDKLVV LECYVRKDLV YTKANPTFHH WKVDNRKFGL TFQSPADARA FDRGVRKAIE DLIEGSTTSS STIHNEAELG DDDVFTTATD SSSNSSQKRE QPTRTISSPT SCEHRRIYTL GHLHDSYPTD HYHLDQPMPR PYRQVSFPDD DEEIVRINPR EKIWMTGYED YRHAPVRGKY PDPSEDADSS YVRFAKGEVP KHDYNYPYVD SSDFGLGEDP KGRGGSVIKT QPSRGKSRRR KEDGERSRCV YCRDMFNHEE NRRGHCQDAP DSVRTCIRRV SCMWCADSML YHCMSDPEGD YTDPCSCDTS DEKFCLRWMA LIALSFLAPC MCCYLPLRAC YHCGVMCRCC GGKHKAAA //