PKDCC_HUMAN
ID PKDCC_HUMAN Reviewed; 493 AA.
AC Q504Y2; D6W5A0; Q96I09;
DT 28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT 23-MAR-2010, sequence version 2.
DT 03-AUG-2022, entry version 135.
DE RecName: Full=Extracellular tyrosine-protein kinase PKDCC {ECO:0000305};
DE EC=2.7.10.2 {ECO:0000269|PubMed:25171405};
DE AltName: Full=Protein kinase domain-containing protein, cytoplasmic {ECO:0000312|HGNC:HGNC:25123};
DE AltName: Full=Protein kinase-like protein SgK493;
DE AltName: Full=Sugen kinase 493;
DE AltName: Full=Vertebrate lonesome kinase {ECO:0000250|UniProtKB:Q5RJI4};
DE Flags: Precursor;
GN Name=PKDCC {ECO:0000312|HGNC:HGNC:25123};
GN Synonyms=SGK493, VLK {ECO:0000250|UniProtKB:Q5RJI4};
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 [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 [2]
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 129-493.
RC TISSUE=Muscle;
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 IDENTIFICATION.
RX PubMed=12471243; DOI=10.1126/science.1075762;
RA Manning G., Whyte D.B., Martinez R., Hunter T., Sudarsanam S.;
RT "The protein kinase complement of the human genome.";
RL Science 298:1912-1934(2002).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=25171405; DOI=10.1016/j.cell.2014.06.048;
RA Bordoli M.R., Yum J., Breitkopf S.B., Thon J.N., Italiano J.E. Jr.,
RA Xiao J., Worby C., Wong S.K., Lin G., Edenius M., Keller T.L., Asara J.M.,
RA Dixon J.E., Yeo C.Y., Whitman M.;
RT "A secreted tyrosine kinase acts in the extracellular environment.";
RL Cell 158:1033-1044(2014).
RN [6]
RP INVOLVEMENT IN RLSDF, AND VARIANT RLSDF 217-TYR--GLY-493 DEL.
RX PubMed=30478137; DOI=10.1136/jmedgenet-2018-105639;
RA Sajan S.A., Ganesh J., Shinde D.N., Powis Z., Scarano M.I., Stone J.,
RA Winter S., Tang S.;
RT "Biallelic disruption of PKDCC is associated with a skeletal disorder
RT characterised by rhizomelic shortening of extremities and dysmorphic
RT features.";
RL J. Med. Genet. 56:850-854(2019).
CC -!- FUNCTION: Secreted tyrosine-protein kinase that mediates
CC phosphorylation of extracellular proteins and endogenous proteins in
CC the secretory pathway, which is essential for patterning at
CC organogenesis stages. Mediates phosphorylation of MMP1, MMP13, MMP14,
CC MMP19 and ERP29 (PubMed:25171405). Probably plays a role in platelets:
CC rapidly and quantitatively secreted from platelets in response to
CC stimulation of platelet degranulation (PubMed:25171405). May also have
CC serine/threonine protein kinase activity. Required for longitudinal
CC bone growth through regulation of chondrocyte differentiation. May be
CC indirectly involved in protein transport from the Golgi apparatus to
CC the plasma membrane (By similarity). {ECO:0000250|UniProtKB:Q5RJI4,
CC ECO:0000269|PubMed:25171405}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2;
CC Evidence={ECO:0000269|PubMed:25171405};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10597;
CC Evidence={ECO:0000269|PubMed:25171405};
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:25171405}. Golgi
CC apparatus {ECO:0000250|UniProtKB:Q5RJI4}.
CC -!- TISSUE SPECIFICITY: Highly expressed in platelets.
CC {ECO:0000269|PubMed:25171405}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q5RJI4}.
CC -!- PTM: Phosphorylated on tyrosines; probably via autophosphorylation.
CC {ECO:0000250|UniProtKB:Q5RJI4}.
CC -!- DISEASE: Rhizomelic limb shortening with dysmorphic features (RLSDF)
CC [MIM:618821]: An autosomal recessive skeletal dysplasia characterized
CC by rhizomelic shortening of limbs as well as variable dysmorphic
CC features, including macrocephaly, short neck, micrognathia, mild
CC proptosis, downslanting palpebral fissures, depressed or broad nasal
CC bridge and long philtrum. {ECO:0000269|PubMed:30478137}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH94697.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAI10514.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAI10515.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AC013480; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471053; EAX00325.1; -; Genomic_DNA.
DR EMBL; CH471053; EAX00326.1; -; Genomic_DNA.
DR EMBL; BC007901; AAH07901.2; -; mRNA.
DR EMBL; BC062988; AAH62988.1; -; mRNA.
DR EMBL; BC094697; AAH94697.1; ALT_INIT; mRNA.
DR EMBL; BC110513; AAI10514.1; ALT_INIT; mRNA.
DR EMBL; BC110514; AAI10515.1; ALT_INIT; mRNA.
DR CCDS; CCDS33186.2; -.
DR RefSeq; NP_612379.2; NM_138370.2.
DR AlphaFoldDB; Q504Y2; -.
DR SMR; Q504Y2; -.
DR BioGRID; 124837; 3.
DR IntAct; Q504Y2; 14.
DR STRING; 9606.ENSP00000294964; -.
DR GlyGen; Q504Y2; 6 sites.
DR iPTMnet; Q504Y2; -.
DR PhosphoSitePlus; Q504Y2; -.
DR BioMuta; PKDCC; -.
DR DMDM; 292495024; -.
DR jPOST; Q504Y2; -.
DR MassIVE; Q504Y2; -.
DR PaxDb; Q504Y2; -.
DR PeptideAtlas; Q504Y2; -.
DR PRIDE; Q504Y2; -.
DR Antibodypedia; 29709; 66 antibodies from 21 providers.
DR DNASU; 91461; -.
DR Ensembl; ENST00000294964.6; ENSP00000294964.5; ENSG00000162878.13.
DR GeneID; 91461; -.
DR KEGG; hsa:91461; -.
DR MANE-Select; ENST00000294964.6; ENSP00000294964.5; NM_138370.3; NP_612379.2.
DR UCSC; uc002rsg.4; human.
DR CTD; 91461; -.
DR DisGeNET; 91461; -.
DR GeneCards; PKDCC; -.
DR HGNC; HGNC:25123; PKDCC.
DR HPA; ENSG00000162878; Tissue enhanced (skeletal).
DR MalaCards; PKDCC; -.
DR MIM; 614150; gene.
DR MIM; 618821; phenotype.
DR neXtProt; NX_Q504Y2; -.
DR OpenTargets; ENSG00000162878; -.
DR PharmGKB; PA165697259; -.
DR VEuPathDB; HostDB:ENSG00000162878; -.
DR eggNOG; KOG1187; Eukaryota.
DR GeneTree; ENSGT00390000001205; -.
DR HOGENOM; CLU_044025_1_0_1; -.
DR InParanoid; Q504Y2; -.
DR OMA; CESHVQC; -.
DR OrthoDB; 490155at2759; -.
DR PhylomeDB; Q504Y2; -.
DR TreeFam; TF329248; -.
DR PathwayCommons; Q504Y2; -.
DR SignaLink; Q504Y2; -.
DR BioGRID-ORCS; 91461; 12 hits in 1075 CRISPR screens.
DR ChiTaRS; PKDCC; human.
DR GenomeRNAi; 91461; -.
DR Pharos; Q504Y2; Tbio.
DR PRO; PR:Q504Y2; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q504Y2; protein.
DR Bgee; ENSG00000162878; Expressed in right ovary and 165 other tissues.
DR ExpressionAtlas; Q504Y2; baseline and differential.
DR Genevisible; Q504Y2; HS.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; IDA:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; ISS:UniProtKB.
DR GO; GO:0030282; P:bone mineralization; IEA:Ensembl.
DR GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR GO; GO:0048566; P:embryonic digestive tract development; ISS:UniProtKB.
DR GO; GO:0035108; P:limb morphogenesis; IEA:Ensembl.
DR GO; GO:0048286; P:lung alveolus development; ISS:UniProtKB.
DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl.
DR GO; GO:0042997; P:negative regulation of Golgi to plasma membrane protein transport; ISS:UniProtKB.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:0030501; P:positive regulation of bone mineralization; ISS:UniProtKB.
DR GO; GO:0032332; P:positive regulation of chondrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0060021; P:roof of mouth development; ISS:UniProtKB.
DR GO; GO:0001501; P:skeletal system development; IMP:UniProtKB.
DR InterPro; IPR022049; FAM69_kinase_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR042983; PKDCC.
DR InterPro; IPR000719; Prot_kinase_dom.
DR PANTHER; PTHR46448; PTHR46448; 1.
DR Pfam; PF12260; PIP49_C; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PE 1: Evidence at protein level;
KW ATP-binding; Developmental protein; Differentiation; Disease variant;
KW Glycoprotein; Golgi apparatus; Kinase; Nucleotide-binding; Osteogenesis;
KW Phosphoprotein; Protein transport; Reference proteome; Secreted; Signal;
KW Transferase; Transport; Tyrosine-protein kinase.
FT SIGNAL 1..32
FT /evidence="ECO:0000255"
FT CHAIN 33..493
FT /note="Extracellular tyrosine-protein kinase PKDCC"
FT /id="PRO_0000263010"
FT DOMAIN 138..493
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 28..128
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 32..46
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 54..68
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 95..126
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 278
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 144..152
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 166
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 148
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q5RJI4"
FT MOD_RES 177
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q5RJI4"
FT CARBOHYD 137
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 320
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 369
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 400
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 460
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 484
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 217..493
FT /note="Missing (in RLSDF)"
FT /evidence="ECO:0000269|PubMed:30478137"
FT /id="VAR_083938"
SQ SEQUENCE 493 AA; 54132 MW; 9E6F2AF7BECDA26C CRC64;
MRRRRAAVAA GFCASFLLGS VLNVLFAPGS EPPRPGQSPE PSPAPGPGRR GGRGELARQI
RARYEEVQRY SRGGPGPGAG RPERRRLMDL APGGPGLPRP RPPWARPLSD GAPGWPPAPG
PGSPGPGPRL GCAALRNVSG AQYMGSGYTK AVYRVRLPGG AAVALKAVDF SGHDLGSCVR
EFGVRRGCYR LAAHKLLKEM VLLERLRHPN VLQLYGYCYQ DSEDIPDTLT TITELGAPVE
MIQLLQTSWE DRFRICLSLG RLLHHLAHSP LGSVTLLDFR PRQFVLVDGE LKVTDLDDAR
VEETPCAGST DCILEFPARN FTLPCSAQGW CEGMNEKRNL YNAYRFFFTY LLPHSAPPSL
RPLLDSIVNA TGELAWGVDE TLAQLEKVLH LYRSGQYLQN STASSSTEYQ CIPDSTIPQE
DYRCWPSYHH GSCLLSVFNL AEAVDVCESH AQCRAFVVTN QTTWTGRQLV FFKTGWSQVV
PDPNKTTYVK ASG
