HIPK2_MOUSE
ID HIPK2_MOUSE Reviewed; 1196 AA.
AC Q9QZR5; O88905; Q99P45; Q99P46; Q9D2E6; Q9D474; Q9EQL2; Q9QZR4;
DT 27-APR-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-APR-2001, sequence version 2.
DT 03-AUG-2022, entry version 203.
DE RecName: Full=Homeodomain-interacting protein kinase 2;
DE EC=2.7.11.1;
DE AltName: Full=Nuclear body-associated kinase 1;
DE AltName: Full=Sialophorin tail-associated nuclear serine/threonine-protein kinase;
GN Name=Hipk2; Synonyms=Nbak1, Stank;
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), SUBCELLULAR LOCATION, INTERACTION
RP WITH NKX1-2 AND NKX2-5, AND MUTAGENESIS OF LYS-228.
RC STRAIN=BALB/cJ;
RX PubMed=9748262; DOI=10.1074/jbc.273.40.25875;
RA Kim Y.H., Choi C.Y., Lee S.-J., Conti M.A., Kim Y.;
RT "Homeodomain-interacting protein kinases, a novel family of co-repressors
RT for homeodomain transcription factors.";
RL J. Biol. Chem. 273:25875-25879(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), INTERACTION WITH SPN/CD43
RP CYTOPLASMIC TAIL (ISOFORM 2), TISSUE SPECIFICITY, SUBCELLULAR LOCATION
RP (ISOFORM 2), AND INDUCTION.
RC STRAIN=BALB/cJ; TISSUE=Heart;
RX PubMed=11078605; DOI=10.1006/cimm.2000.1716;
RA Wang W., Link V., Green J.M.;
RT "Identification and cloning of a CD43-associated serine/threonine kinase.";
RL Cell. Immunol. 205:34-39(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RX PubMed=11267674; DOI=10.1016/s0167-4781(00)00308-0;
RA Wang Y., Hofmann T.G., Runkel L., Haaf T., Schaller H., Debatin K.-M.,
RA Hug H.;
RT "Isolation and characterization of cDNAs for the protein kinase HIPK2.";
RL Biochim. Biophys. Acta 1518:168-172(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), TISSUE SPECIFICITY, AND
RP SUBCELLULAR LOCATION.
RC TISSUE=Heart;
RX PubMed=14990717; DOI=10.1128/jvi.78.6.2984-2993.2004;
RA Giraud S., Diaz-Latoud C., Hacot S., Textoris J., Bourette R.P.,
RA Diaz J.-J.;
RT "US11 of herpes simplex virus type 1 interacts with HIPK2 and antagonizes
RT HIPK2-induced cell growth arrest.";
RL J. Virol. 78:2984-2993(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RA Sather S.L., Johnson N.L., Johnson G.L.;
RT "Protein kinases associated with PML/CBP nuclear bodies and filamentous
RT threads regulate transcription and inhibit cell growth.";
RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 5).
RC STRAIN=C57BL/6J; TISSUE=Testis;
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 [7]
RP SUBCELLULAR LOCATION, INTERACTION WITH UBE2I, SUMOYLATION, AND MUTAGENESIS
RP OF LYS-1189.
RX PubMed=10535925; DOI=10.1073/pnas.96.22.12350;
RA Kim Y.H., Choi C.Y., Kim Y.;
RT "Covalent modification of the homeodomain-interacting protein kinase 2
RT (HIPK2) by the ubiquitin-like protein SUMO-1.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:12350-12355(1999).
RN [8]
RP INTERACTION WITH HMGA1, FUNCTION, PHOSPHORYLATION, AUTOPHOSPHORYLATION, AND
RP MUTAGENESIS OF LYS-228.
RX PubMed=11593421; DOI=10.1038/sj.onc.1204635;
RA Pierantoni G.M., Fedele M., Pentimalli F., Benvenuto G., Pero R.,
RA Viglietto G., Santoro M., Chiariotti L., Fusco A.;
RT "High mobility group I (Y) proteins bind HIPK2, a serine-threonine kinase
RT protein which inhibits cell growth.";
RL Oncogene 20:6132-6141(2001).
RN [9]
RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RX PubMed=11798164; DOI=10.1006/bbrc.2001.6310;
RA Pierantoni G.M., Bulfone A., Pentimalli F., Fedele M., Iuliano R.,
RA Santoro M., Chiariotti L., Ballabio A., Fusco A.;
RT "The homeodomain-interacting protein kinase 2 gene is expressed late in
RT embryogenesis and preferentially in retina, muscle, and neural tissues.";
RL Biochem. Biophys. Res. Commun. 290:942-947(2002).
RN [10]
RP FUNCTION, INTERACTION WITH TP53, AUTOPHOSPHORYLATION, AND MUTAGENESIS OF
RP LYS-228.
RX PubMed=11780126; DOI=10.1038/ncb714;
RA D'Orazi G., Cecchinelli B., Bruno T., Manni I., Higashimoto Y., Saito S.,
RA Gostissa M., Coen S., Marchetti A., Del Sal G., Piaggio G., Fanciulli M.,
RA Appella E., Soddu S.;
RT "Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and
RT mediates apoptosis.";
RL Nat. Cell Biol. 4:11-19(2002).
RN [11]
RP FUNCTION, AND INTERACTION WITH CTBP1.
RX PubMed=14567915; DOI=10.1016/s0092-8674(03)00802-x;
RA Zhang Q., Yoshimatsu Y., Hildebrand J., Frisch S.M., Goodman R.H.;
RT "Homeodomain interacting protein kinase 2 promotes apoptosis by
RT downregulating the transcriptional corepressor CtBP.";
RL Cell 115:177-186(2003).
RN [12]
RP INTERACTION WITH AXIN1, AND IDENTIFICATION IN A COMPLEX WITH TP53 AND
RP AXIN1.
RX PubMed=15526030; DOI=10.1038/sj.emboj.7600475;
RA Rui Y., Xu Z., Lin S., Li Q., Rui H., Luo W., Zhou H.-M., Cheung P.-Y.,
RA Wu Z., Ye Z., Li P., Han J., Lin S.-C.;
RT "Axin stimulates p53 functions by activation of HIPK2 kinase through
RT multimeric complex formation.";
RL EMBO J. 23:4583-4594(2004).
RN [13]
RP FUNCTION IN WNT SIGNALING, INTERACTION WITH NLK AND MYB, AND MUTAGENESIS OF
RP LYS-228.
RX PubMed=15082531; DOI=10.1101/gad.1170604;
RA Kanei-Ishii C., Ninomiya-Tsuji J., Tanikawa J., Nomura T., Ishitani T.,
RA Kishida S., Kokura K., Kurahashi T., Ichikawa-Iwata E., Kim Y.,
RA Matsumoto K., Ishii S.;
RT "Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via
RT TAK1, HIPK2, and NLK.";
RL Genes Dev. 18:816-829(2004).
RN [14]
RP FUNCTION, INTERACTION WITH POU4F1; POU4F2 AND POU4F3, AND DEVELOPMENTAL
RP STAGE.
RX PubMed=15492043; DOI=10.1083/jcb.200406131;
RA Wiggins A.K., Wei G., Doxakis E., Wong C., Tang A.A., Zang K., Luo E.J.,
RA Neve R.L., Reichardt L.F., Huang E.J.;
RT "Interaction of Brn3a and HIPK2 mediates transcriptional repression of
RT sensory neuron survival.";
RL J. Cell Biol. 167:257-267(2004).
RN [15]
RP FUNCTION AS KINASE AND IN ANGIOGENESIS, AND INTERACTION WITH RUNX1 AND
RP EP300.
RX PubMed=16917507; DOI=10.1038/sj.emboj.7601273;
RA Aikawa Y., Nguyen L.A., Isono K., Takakura N., Tagata Y., Schmitz M.L.,
RA Koseki H., Kitabayashi I.;
RT "Roles of HIPK1 and HIPK2 in AML1- and p300-dependent transcription,
RT hematopoiesis and blood vessel formation.";
RL EMBO J. 25:3955-3965(2006).
RN [16]
RP INDUCTION BY ZINC DURING HYPOXIA.
RX PubMed=19714248; DOI=10.1371/journal.pone.0006819;
RA Nardinocchi L., Puca R., Sacchi A., Rechavi G., Givol D., D'Orazi G.;
RT "Targeting hypoxia in cancer cells by restoring homeodomain interacting
RT protein-kinase 2 and p53 activity and suppressing HIF-1alpha.";
RL PLoS ONE 4:E6819-E6819(2009).
RN [17]
RP FUNCTION AS CTNNB1 KINASE, AND DISRUPTION PHENOTYPE.
RX PubMed=20307497; DOI=10.1016/j.bbrc.2010.03.099;
RA Kim E.-A., Kim J.E., Sung K.S., Choi D.W., Lee B.J., Choi C.Y.;
RT "Homeodomain-interacting protein kinase 2 (HIPK2) targets beta-catenin for
RT phosphorylation and proteasomal degradation.";
RL Biochem. Biophys. Res. Commun. 394:966-971(2010).
RN [18]
RP FUNCTION AS PDX1 KINASE.
RX PubMed=20637728; DOI=10.1016/j.bbrc.2010.07.035;
RA An R., da Silva Xavier G., Semplici F., Vakhshouri S., Hao H.X., Rutter J.,
RA Pagano M.A., Meggio F., Pinna L.A., Rutter G.A.;
RT "Pancreatic and duodenal homeobox 1 (PDX1) phosphorylation at serine-269 is
RT HIPK2-dependent and affects PDX1 subnuclear localization.";
RL Biochem. Biophys. Res. Commun. 399:155-161(2010).
RN [19]
RP FUNCTION, DISRUPTION PHENOTYPE, AND DEVELOPMENTAL STAGE.
RX PubMed=20231426; DOI=10.1182/blood-2009-07-235093;
RA Hattangadi S.M., Burke K.A., Lodish H.F.;
RT "Homeodomain-interacting protein kinase 2 plays an important role in normal
RT terminal erythroid differentiation.";
RL Blood 115:4853-4861(2010).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-827, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Pancreas;
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 [21]
RP FUNCTION IN EYE DEVELOPMENT, DEVELOPMENTAL STAGE, SUBCELLULAR LOCATION, AND
RP DISRUPTION PHENOTYPE.
RX PubMed=20579985; DOI=10.1016/j.febslet.2010.06.020;
RA Inoue T., Kagawa T., Inoue-Mochita M., Isono K., Ohtsu N., Nobuhisa I.,
RA Fukushima M., Tanihara H., Taga T.;
RT "Involvement of the Hipk family in regulation of eyeball size, lens
RT formation and retinal morphogenesis.";
RL FEBS Lett. 584:3233-3238(2010).
RN [22]
RP PHOSPHORYLATION AT SER-16; SER-118; SER-135; THR-141; THR-252; THR-273;
RP TYR-361; SER-441; THR-482; THR-517; THR-566; SER-634; SER-668; THR-687;
RP SER-815; SER-827; SER-934; SER-991; SER-993; SER-1042; SER-1153 AND
RP SER-1186, ACTIVITY REGULATION, AND MUTAGENESIS OF TYR-361.
RX PubMed=23485397; DOI=10.1016/j.bbamcr.2013.02.018;
RA Siepi F., Gatti V., Camerini S., Crescenzi M., Soddu S.;
RT "HIPK2 catalytic activity and subcellular localization are regulated by
RT activation-loop Y354 autophosphorylation.";
RL Biochim. Biophys. Acta 1833:1443-1453(2013).
CC -!- FUNCTION: Serine/threonine-protein kinase involved in transcription
CC regulation, p53/TP53-mediated cellular apoptosis and regulation of the
CC cell cycle. Acts as a corepressor of several transcription factors,
CC including SMAD1 and POU4F1/Brn3a and probably NK homeodomain
CC transcription factors. Phosphorylates PDX1, ATF1, PML, p53/TP53, CREB1,
CC CTBP1, CBX4, RUNX1, EP300, CTNNB1, HMGA1 and ZBTB4. Inhibits cell
CC growth and promotes apoptosis through the activation of p53/TP53 both
CC at the transcription level and at the protein level (by phosphorylation
CC and indirect acetylation). The phosphorylation of p53/TP53 may be
CC mediated by a p53/TP53-HIPK2-AXIN1 complex. Involved in the response to
CC hypoxia by acting as a transcriptional co-suppressor of HIF1A. Mediates
CC transcriptional activation of TP73. In response to TGFB, cooperates
CC with DAXX to activate JNK. Negative regulator through phosphorylation
CC and subsequent proteasomal degradation of CTNNB1 and the antiapoptotic
CC factor CTBP1. In the Wnt/beta-catenin signaling pathway acts as an
CC intermediate kinase between MAP3K7/TAK1 and NLK to promote the
CC proteasomal degradation of MYB. Phosphorylates CBX4 upon DNA damage and
CC promotes its E3 SUMO-protein ligase activity. Activates CREB1 and ATF1
CC transcription factors by phosphorylation in response to genotoxic
CC stress. In response to DNA damage, stabilizes PML by phosphorylation.
CC PML, HIPK2 and FBXO3 may act synergically to activate p53/TP53-
CC dependent transactivation. Promotes angiogenesis, and is involved in
CC erythroid differentiation, especially during fetal liver
CC erythropoiesis. Phosphorylation of RUNX1 and EP300 stimulates EP300
CC transcription regulation activity. Triggers ZBTB4 protein degradation
CC in response to DNA damage. Modulates HMGA1 DNA-binding affinity. In
CC response to high glucose, triggers phosphorylation-mediated subnuclear
CC localization shifting of PDX1. Involved in the regulation of eye size,
CC lens formation and retinal lamination during late embryogenesis.
CC {ECO:0000269|PubMed:11593421, ECO:0000269|PubMed:11780126,
CC ECO:0000269|PubMed:14567915, ECO:0000269|PubMed:15082531,
CC ECO:0000269|PubMed:15492043, ECO:0000269|PubMed:16917507,
CC ECO:0000269|PubMed:20231426, ECO:0000269|PubMed:20307497,
CC ECO:0000269|PubMed:20579985, ECO:0000269|PubMed:20637728}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1;
CC -!- SUBUNIT: Interacts with CREB1, SIAH1, WSB1, CBX4, TRADD, p53/TP53,
CC TP73, TP63, CREBBP, DAXX, P53DINP1, SKI, SMAD1, SMAD2 and SMAD3, but
CC not SMAD4. Interacts with SP100; positively regulates TP53-dependent
CC transcription (By similarity). Interacts with ATF1, PML, RUNX1, EP300,
CC NKX1-2, NKX2-5, UBE2I, HMGA1, CTBP1, AXIN1, NLK, MYB, POU4F1, POU4F2,
CC POU4F3, UBE2I, UBL1 and ZBTB4. Probably part of a complex consisting of
CC p53/TP53, HIPK2 and AXIN1. {ECO:0000250|UniProtKB:Q9H2X6,
CC ECO:0000269|PubMed:10535925, ECO:0000269|PubMed:11078605,
CC ECO:0000269|PubMed:11593421, ECO:0000269|PubMed:11780126,
CC ECO:0000269|PubMed:14567915, ECO:0000269|PubMed:15082531,
CC ECO:0000269|PubMed:15492043, ECO:0000269|PubMed:15526030,
CC ECO:0000269|PubMed:16917507, ECO:0000269|PubMed:9748262}.
CC -!- SUBUNIT: [Isoform 2]: Interacts with SPN/CD43 cytoplasmic tail.
CC {ECO:0000269|PubMed:11078605}.
CC -!- INTERACTION:
CC Q9QZR5; Q8CFN5: Mef2c; NbExp=5; IntAct=EBI-366905, EBI-643797;
CC Q9QZR5; P06876: Myb; NbExp=2; IntAct=EBI-366905, EBI-366934;
CC Q9QZR5; O54949: Nlk; NbExp=2; IntAct=EBI-366905, EBI-366894;
CC Q9QZR5; P51608: MECP2; Xeno; NbExp=3; IntAct=EBI-366905, EBI-1189067;
CC Q9QZR5; Q9Y6I7: WSB1; Xeno; NbExp=5; IntAct=EBI-366905, EBI-1171494;
CC -!- SUBCELLULAR LOCATION: Nucleus, PML body {ECO:0000269|PubMed:10535925,
CC ECO:0000269|PubMed:11078605, ECO:0000269|PubMed:14990717,
CC ECO:0000269|PubMed:20579985, ECO:0000269|PubMed:9748262}. Cytoplasm
CC {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus
CC {ECO:0000269|PubMed:11078605}. Cytoplasm {ECO:0000269|PubMed:11078605}.
CC Note=Isoform 2 seems to be both nuclear and cytoplasmic.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1; Synonyms=Nbak1b, b;
CC IsoId=Q9QZR5-1; Sequence=Displayed;
CC Name=2; Synonyms=Nbak1a, a;
CC IsoId=Q9QZR5-2; Sequence=VSP_004808;
CC Name=3;
CC IsoId=Q9QZR5-3; Sequence=VSP_013135, VSP_013137;
CC Name=4;
CC IsoId=Q9QZR5-4; Sequence=VSP_013135, VSP_004808;
CC Name=5;
CC IsoId=Q9QZR5-5; Sequence=VSP_013136, VSP_013138, VSP_013139;
CC -!- TISSUE SPECIFICITY: Ubiquitous. Abundant in muscle, heart, small
CC intestine, stomach, kidney and brain; and low in testis, skin and lung.
CC {ECO:0000269|PubMed:11078605, ECO:0000269|PubMed:11798164,
CC ECO:0000269|PubMed:14990717}.
CC -!- DEVELOPMENTAL STAGE: At 15 dpc-17 dpc, mainly in the developing retina,
CC telencephalon and myoblasts. At 12.5 dpc, detected in the developing
CC trigeminal and dorsal root ganglia, and in the developing spinal cord
CC (at protein level). Highly induced during primary fetal liver
CC erythropoiesis. Expressed in the inner retina during late
CC embryogenesis, in nucleus. Highest levels at 14.5 dpc for isoform 2 and
CC P12.5 for isoform 1. {ECO:0000269|PubMed:11798164,
CC ECO:0000269|PubMed:15492043, ECO:0000269|PubMed:20231426,
CC ECO:0000269|PubMed:20579985}.
CC -!- INDUCTION: During T-cell activation. {ECO:0000269|PubMed:11078605,
CC ECO:0000269|PubMed:19714248}.
CC -!- PTM: Sumoylated. When conjugated it is directed to nuclear speckles.
CC Desumoylated by SENP1. Sumoylation on Lys-32 is promoted by the E3
CC SUMO-protein ligase CBX4 (By similarity). {ECO:0000250}.
CC -!- PTM: Autophosphorylation at Tyr-361 in the activation loop activates
CC the kinase and promotes nuclear localization.
CC {ECO:0000269|PubMed:23485397}.
CC -!- PTM: Ubiquitinated by FBXO3, WSB1 and SIAH1, leading to rapid
CC proteasome-dependent degradation. The degradation mediated by FBXO3,
CC but not ubiquitination, is prevented in the presence of PML. The
CC degradation mediated by WSB1 and SIAH1 is reversibly reduced upon DNA
CC damage (By similarity). {ECO:0000250}.
CC -!- PTM: Cleaved at Asp-923 and Asp-984 by CASP6 in a p53/TP53-dependent
CC manner. The cleaved form lacks the autoinhibitory C-terminal domain
CC (AID), resulting in a hyperactive kinase, which potentiates p53/TP53
CC Ser-46 phosphorylation and subsequent activation of the cell death
CC machinery.
CC -!- DISRUPTION PHENOTYPE: Inhibited terminal erythroid cell proliferation
CC and terminal enucleation, as well as reduced accumulation of
CC hemoglobin. Impaired transcription of many genes involved in cell
CC proliferation and apoptosis, and of erythroid-specific genes involved
CC in hemoglobin biosynthesis, such as HBA and SLC25A37/MFRN. Enhanced
CC stability of CTNNB1; accumulation of beta-catenin leading to the
CC potentiation of beta-catenin-mediated cell proliferation and tumor
CC formation. Small eyes with deficient lens, abnormal retinal lamination,
CC and thickened retinas. {ECO:0000269|PubMed:20231426,
CC ECO:0000269|PubMed:20307497, ECO:0000269|PubMed:20579985}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CMGC Ser/Thr
CC protein kinase family. HIPK subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC63011.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AF077659; AAC63011.1; ALT_FRAME; mRNA.
DR EMBL; AF273680; AAG02078.1; -; mRNA.
DR EMBL; AF208292; AAG41237.1; -; mRNA.
DR EMBL; AF333791; AAK07649.1; -; mRNA.
DR EMBL; AF333792; AAK07650.1; -; mRNA.
DR EMBL; AF170301; AAD52566.1; -; mRNA.
DR EMBL; AF170302; AAD52567.1; -; mRNA.
DR EMBL; AK016742; BAB30405.1; -; mRNA.
DR EMBL; AK019821; BAB31866.1; -; mRNA.
DR CCDS; CCDS20017.2; -. [Q9QZR5-1]
DR CCDS; CCDS80527.1; -. [Q9QZR5-2]
DR PIR; T17088; T17088.
DR RefSeq; NP_001129537.1; NM_001136065.2.
DR RefSeq; NP_001281072.1; NM_001294143.1. [Q9QZR5-2]
DR RefSeq; NP_001281073.1; NM_001294144.1.
DR RefSeq; NP_034563.2; NM_010433.2. [Q9QZR5-1]
DR AlphaFoldDB; Q9QZR5; -.
DR SMR; Q9QZR5; -.
DR BioGRID; 200307; 10.
DR DIP; DIP-31712N; -.
DR IntAct; Q9QZR5; 12.
DR MINT; Q9QZR5; -.
DR STRING; 10090.ENSMUSP00000124133; -.
DR iPTMnet; Q9QZR5; -.
DR PhosphoSitePlus; Q9QZR5; -.
DR jPOST; Q9QZR5; -.
DR MaxQB; Q9QZR5; -.
DR PaxDb; Q9QZR5; -.
DR PRIDE; Q9QZR5; -.
DR ProteomicsDB; 269598; -. [Q9QZR5-1]
DR ProteomicsDB; 269599; -. [Q9QZR5-2]
DR ProteomicsDB; 269600; -. [Q9QZR5-3]
DR ProteomicsDB; 269601; -. [Q9QZR5-4]
DR ProteomicsDB; 269602; -. [Q9QZR5-5]
DR Antibodypedia; 9921; 365 antibodies from 33 providers.
DR DNASU; 15258; -.
DR Ensembl; ENSMUST00000161779; ENSMUSP00000124133; ENSMUSG00000061436. [Q9QZR5-1]
DR Ensembl; ENSMUST00000162359; ENSMUSP00000125150; ENSMUSG00000061436. [Q9QZR5-2]
DR GeneID; 15258; -.
DR KEGG; mmu:15258; -.
DR UCSC; uc009bkw.3; mouse. [Q9QZR5-4]
DR UCSC; uc009bkx.2; mouse. [Q9QZR5-1]
DR UCSC; uc009blb.3; mouse. [Q9QZR5-3]
DR CTD; 28996; -.
DR MGI; MGI:1314872; Hipk2.
DR VEuPathDB; HostDB:ENSMUSG00000061436; -.
DR eggNOG; KOG0667; Eukaryota.
DR GeneTree; ENSGT00940000157742; -.
DR InParanoid; Q9QZR5; -.
DR OMA; THSKVYN; -.
DR OrthoDB; 59821at2759; -.
DR PhylomeDB; Q9QZR5; -.
DR TreeFam; TF105417; -.
DR BRENDA; 2.7.11.1; 3474.
DR Reactome; R-MMU-3899300; SUMOylation of transcription cofactors.
DR Reactome; R-MMU-6804756; Regulation of TP53 Activity through Phosphorylation.
DR Reactome; R-MMU-8939243; RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known.
DR Reactome; R-MMU-9022692; Regulation of MECP2 expression and activity.
DR BioGRID-ORCS; 15258; 1 hit in 78 CRISPR screens.
DR ChiTaRS; Hipk2; mouse.
DR PRO; PR:Q9QZR5; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; Q9QZR5; protein.
DR Bgee; ENSMUSG00000061436; Expressed in vestibular membrane of cochlear duct and 278 other tissues.
DR ExpressionAtlas; Q9QZR5; baseline and differential.
DR Genevisible; Q9QZR5; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0016604; C:nuclear body; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0016605; C:PML body; ISO:MGI.
DR GO; GO:0090575; C:RNA polymerase II transcription regulator complex; IMP:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; IDA:BHF-UCL.
DR GO; GO:0004713; F:protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0061629; F:RNA polymerase II-specific DNA-binding transcription factor binding; IPI:BHF-UCL.
DR GO; GO:0046332; F:SMAD binding; ISO:MGI.
DR GO; GO:0003714; F:transcription corepressor activity; IDA:UniProtKB.
DR GO; GO:0046790; F:virion binding; ISS:UniProtKB.
DR GO; GO:0008344; P:adult locomotory behavior; IMP:MGI.
DR GO; GO:0007628; P:adult walking behavior; IMP:MGI.
DR GO; GO:0009952; P:anterior/posterior pattern specification; IGI:MGI.
DR GO; GO:0008283; P:cell population proliferation; IGI:MGI.
DR GO; GO:0006978; P:DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator; ISO:MGI.
DR GO; GO:0048596; P:embryonic camera-type eye morphogenesis; IMP:DFLAT.
DR GO; GO:0060059; P:embryonic retina morphogenesis in camera-type eye; IMP:DFLAT.
DR GO; GO:0042771; P:intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; IGI:MGI.
DR GO; GO:0061072; P:iris morphogenesis; IMP:DFLAT.
DR GO; GO:0060235; P:lens induction in camera-type eye; IMP:DFLAT.
DR GO; GO:0030514; P:negative regulation of BMP signaling pathway; ISO:MGI.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IMP:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:2000059; P:negative regulation of ubiquitin-dependent protein catabolic process; ISO:MGI.
DR GO; GO:0051402; P:neuron apoptotic process; IMP:MGI.
DR GO; GO:0030182; P:neuron differentiation; IMP:DFLAT.
DR GO; GO:0018105; P:peptidyl-serine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; IDA:BHF-UCL.
DR GO; GO:0045766; P:positive regulation of angiogenesis; ISO:MGI.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IGI:MGI.
DR GO; GO:0043388; P:positive regulation of DNA binding; IDA:UniProtKB.
DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; IDA:BHF-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; ISS:UniProtKB.
DR GO; GO:0032092; P:positive regulation of protein binding; IDA:BHF-UCL.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IGI:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:BHF-UCL.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:MGI.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0010842; P:retina layer formation; IMP:DFLAT.
DR GO; GO:0060395; P:SMAD protein signal transduction; ISO:MGI.
DR GO; GO:0007224; P:smoothened signaling pathway; IGI:MGI.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IMP:MGI.
DR GO; GO:0050882; P:voluntary musculoskeletal movement; IMP:MGI.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Apoptosis; ATP-binding; Cytoplasm; DNA damage;
KW Isopeptide bond; Kinase; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Serine/threonine-protein kinase; Transcription;
KW Transcription regulation; Transferase; Tumor suppressor; Ubl conjugation.
FT CHAIN 1..1196
FT /note="Homeodomain-interacting protein kinase 2"
FT /id="PRO_0000085997"
FT DOMAIN 199..527
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 50..69
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 97..230
FT /note="Transcriptional corepression"
FT REGION 189..520
FT /note="Interaction with DAXX"
FT /evidence="ECO:0000250"
FT REGION 539..844
FT /note="Interaction with SKI and SMAD1"
FT /evidence="ECO:0000250"
FT REGION 752..897
FT /note="Interaction with POU4F1"
FT /evidence="ECO:0000269|PubMed:15492043"
FT REGION 774..876
FT /note="Interaction with CTBP1"
FT /evidence="ECO:0000269|PubMed:14567915"
FT REGION 787..897
FT /note="Interaction with HMGA1"
FT /evidence="ECO:0000269|PubMed:11593421"
FT REGION 792..847
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 839..934
FT /note="Interaction with TP53 and TP73"
FT /evidence="ECO:0000269|PubMed:11780126"
FT REGION 873..980
FT /note="Localization to nuclear speckles"
FT REGION 873..980
FT /note="Required for localization to nuclear speckles"
FT /evidence="ECO:0000250"
FT REGION 873..907
FT /note="Interaction with UBE2I"
FT /evidence="ECO:0000269|PubMed:10535925"
FT REGION 884..908
FT /note="SUMO interaction motifs (SIM); required for nuclear
FT localization and kinase activity"
FT /evidence="ECO:0000250"
FT REGION 891..963
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 935..1050
FT /note="Interaction with AXIN1"
FT /evidence="ECO:0000269|PubMed:15526030"
FT REGION 984..1196
FT /note="Autoinhibitory domain (AID)"
FT /evidence="ECO:0000250"
FT REGION 991..1058
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 802..805
FT /note="Nuclear localization signal 1 (NLS1)"
FT /evidence="ECO:0000250"
FT MOTIF 832..835
FT /note="Nuclear localization signal 2 (NLS2)"
FT /evidence="ECO:0000250"
FT COMPBIAS 792..833
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 907..956
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 991..1050
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 324
FT /note="Proton acceptor"
FT /evidence="ECO:0000305"
FT BINDING 205..213
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT BINDING 228
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000305"
FT SITE 923..924
FT /note="Cleavage; by CASP6"
FT /evidence="ECO:0000250"
FT SITE 984..985
FT /note="Cleavage; by CASP6"
FT /evidence="ECO:0000250"
FT MOD_RES 16
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 118
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 135
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 141
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 252
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 273
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 361
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 441
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 482
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 517
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 566
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 634
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 668
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 687
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 815
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 827
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 934
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 991
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 993
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 1042
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 1153
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT MOD_RES 1186
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:23485397"
FT CROSSLNK 32
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250"
FT CROSSLNK 32
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9H2X6"
FT CROSSLNK 953
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q9H2X6"
FT CROSSLNK 973
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:Q9H2X6"
FT CROSSLNK 1189
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT VAR_SEQ 1..480
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_013136"
FT VAR_SEQ 1..7
FT /note="Missing (in isoform 3 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:11267674,
FT ECO:0000303|PubMed:16141072"
FT /id="VSP_013135"
FT VAR_SEQ 369..1196
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_013137"
FT VAR_SEQ 594..620
FT /note="Missing (in isoform 2 and isoform 4)"
FT /evidence="ECO:0000303|PubMed:11078605,
FT ECO:0000303|PubMed:11267674, ECO:0000303|PubMed:14990717,
FT ECO:0000303|Ref.5"
FT /id="VSP_004808"
FT VAR_SEQ 595..605
FT /note="APTTSSATLSL -> KSQLIGLSPES (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_013138"
FT VAR_SEQ 606..1196
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_013139"
FT MUTAGEN 228
FT /note="K->R: No enzymatic activity, but still interacts
FT with TP53 and NLK. Blocks the ability to induce cell growth
FT arrest. Decreases corepressor activity."
FT /evidence="ECO:0000269|PubMed:11593421,
FT ECO:0000269|PubMed:11780126, ECO:0000269|PubMed:15082531,
FT ECO:0000269|PubMed:9748262"
FT MUTAGEN 361
FT /note="Y->A: Strongly reduced nuclear localization."
FT /evidence="ECO:0000269|PubMed:23485397"
FT MUTAGEN 1189
FT /note="K->R: Inhibits localization to nuclear speckles."
FT /evidence="ECO:0000269|PubMed:10535925"
FT CONFLICT 460
FT /note="I -> T (in Ref. 1; AAC63011)"
FT /evidence="ECO:0000305"
FT CONFLICT 479
FT /note="V -> G (in Ref. 1; AAC63011)"
FT /evidence="ECO:0000305"
FT CONFLICT 705
FT /note="Missing (in Ref. 3; AAG41237 and 4; AAK07649)"
FT /evidence="ECO:0000305"
FT CONFLICT 719
FT /note="A -> T (in Ref. 1; AAC63011)"
FT /evidence="ECO:0000305"
FT CONFLICT 1120
FT /note="A -> R (in Ref. 1; AAC63011)"
FT /evidence="ECO:0000305"
FT CONFLICT 1132
FT /note="T -> A (in Ref. 4; AAK07650)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1196 AA; 130498 MW; 5C863BE377F3AAEF CRC64;
MAPVYEGMAS HVQVFSPHTL QSSAFCSVKK LKVEPSSNWD MTGYGSHSKV YSQSKNIPPS
QPASTTVSTS LPIPNPSLPY EQTIIFPGST GHIVVTSASS TSVTGQVLGG PHNLMRRSTV
SLLDTYQKCG LKRKSEEIEN TSSVQIIEEH PPMIQNNASG ATVATATTST ATSKNSGSNS
EGDYQLVQHE VLCSMTNTYE VLEFLGRGTF GQVVKCWKRG TNEIVAIKIL KNHPSYARQG
QIEVSILARL STESADDYNF VRAYECFQHK NHTCLVFEML EQNLYDFLKQ NKFSPLPLKY
IRPVLQQVAT ALMKLKSLGL IHADLKPENI MLVDPSRQPY RVKVIDFGSA SHVSKAVCST
YLQSRYYRAP EIILGLPFCE AIDMWSLGCV IAELFLGWPL YPGASEYDQI RYISQTQGLP
AEYLLSAGTK TTRFFNRDTD SPYPLWRLKT PDDHEAETGI KSKEARKYIF NCLDDMAQVN
MTTDLEGSDM LVEKADRREF IDLLKKMLTI DADKRVTPIE TLNHPFVTMT HLLDFPHSAH
VKSCFQNMEI CKRRVNMYDT VNQSKTPFIT HVAPSTSTNL TMTFNNQLTT VHNQAPTTSS
ATLSLANPEV SILNYQSALY QPSAASMAAV APRSMPLQTG TAQICARPDP FQQALIVCPP
GFQGLQASPS KHAGYSVRME NAVPIVTQAP GAQPLQIQPG LLAQQAWPGG AQQILLPPAW
QQLTGVATHT SVQHAAVIPE TMAGTQQLAD WRNTHAHGSH YNPIMQQPAL LTGHVTLPAA
QPLNVGVAHV MRQQPTSTTS SRKSKQHQSS VRNVSTCEVT SSQAISSPQR SKRVKENTPP
RCAMVHSSPA CSTSVTCGWG DVASSTTRER QRQTIVIPDT PSPTVSVITI SSDTDEEEEQ
KHAPTSTVSK QRKNVISCVT VHDSPYSDSS SNTSPYSVQQ RTGHNGTNTL DTKGGLENHC
TGNPRTIIVP PLKTQASEVL VECDSLGPAI SASHHSSSFK SKSSSTVTST SGHSSGSSSG
AIAYRQQRPG PHFQQQQPLN LSQAQQHMAA DRTGSHRRQQ AYITPTMAQA PYTFPHNSPS
HGTVHPHLAA AAHLPTQPHL YTYTAPTALG STGTVAHLVA SQGSARHTVQ HTAYPASIVH
QVPVSMGPRV LPSPTIHPSQ YPAQFAHQTY ISASPASTVY TGYPLSPAKV NQYPYI
