ID   PKDCC_MOUSE             Reviewed;         492 AA.
AC   Q5RJI4; B6F136; Q3UZD3; Q8VBZ6;
DT   28-NOV-2006, integrated into UniProtKB/Swiss-Prot.
DT   23-MAR-2010, sequence version 2.
DT   24-JAN-2024, entry version 144.
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|MGI:MGI:2147077};
DE   AltName: Full=Protein kinase-like protein SgK493;
DE   AltName: Full=Sugen kinase 493;
DE   AltName: Full=Vertebrate lonesome kinase {ECO:0000303|PubMed:19465597};
DE   Flags: Precursor;
GN   Name=Pkdcc {ECO:0000312|MGI:MGI:2147077};
GN   Synonyms=Sgk493, Vlk {ECO:0000303|PubMed:19465597};
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), FUNCTION, TISSUE SPECIFICITY,
RP   DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE, AND ALTERNATIVE SPLICING.
RC   TISSUE=Embryo;
RX   PubMed=19097194; DOI=10.1002/dvdy.21822;
RA   Imuta Y., Nishioka N., Kiyonari H., Sasaki H.;
RT   "Short limbs, cleft palate, and delayed formation of flat proliferative
RT   chondrocytes in mice with targeted disruption of a putative protein kinase
RT   gene, Pkdcc (AW548124).";
RL   Dev. Dyn. 238:210-222(2009).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION,
RP   TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, DISRUPTION PHENOTYPE,
RP   PHOSPHORYLATION AT TYR-148 AND SER-177, AND MUTAGENESIS OF LYS-166.
RX   PubMed=19465597; DOI=10.1242/dev.026435;
RA   Kinoshita M., Era T., Jakt L.M., Nishikawa S.;
RT   "The novel protein kinase Vlk is essential for stromal function of
RT   mesenchymal cells.";
RL   Development 136:2069-2079(2009).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   STRAIN=C57BL/6J, and FVB/N; TISSUE=Brain, and Liver;
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   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 381-492 (ISOFORMS 1/2).
RC   STRAIN=C57BL/6J; TISSUE=Embryo;
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   [5]
RP   FUNCTION.
RX   PubMed=23792766; DOI=10.1016/j.diff.2013.03.002;
RA   Probst S., Zeller R., Zuniga A.;
RT   "The hedgehog target Vlk genetically interacts with Gli3 to regulate
RT   chondrocyte differentiation during mouse long bone development.";
RL   Differentiation 85:121-130(2013).
RN   [6]
RP   FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, GLYCOSYLATION,
RP   PHOSPHORYLATION, AND MUTAGENESIS OF TYR-148; LYS-166; GLU-199 AND ASP-295.
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).
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). May also have serine/threonine
CC       protein kinase activity (PubMed:25171405). Required for longitudinal
CC       bone growth through regulation of chondrocyte differentiation
CC       (PubMed:19097194, PubMed:23792766). May be indirectly involved in
CC       protein transport from the Golgi apparatus to the plasma membrane
CC       (PubMed:19465597). Probably plays a role in platelets: rapidly and
CC       quantitatively secreted from platelets in response to stimulation of
CC       platelet degranulation (PubMed:25171405). {ECO:0000269|PubMed:19097194,
CC       ECO:0000269|PubMed:19465597, ECO:0000269|PubMed:23792766,
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:0000269|PubMed:19465597}. Note=Both secreted and present
CC       in the Golgi apparatus. {ECO:0000269|PubMed:19465597,
CC       ECO:0000269|PubMed:25171405}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q5RJI4-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q5RJI4-2; Sequence=VSP_038822;
CC   -!- TISSUE SPECIFICITY: Strongly expressed in adult heart, liver and testis
CC       with weak expression in brain, spleen, lung and thymus. In the humerus,
CC       strongly expressed in early flat proliferative chondrocytes. In the
CC       embryo, expressed in the anterior visceral endoderm and anterior
CC       primitive streak at 6.5 dpc. At 7.5 dpc, expressed in the anterior
CC       definitive endoderm (ADE) and anterior mesoderm but not in the
CC       notochord. At 8.0 dpc, expressed in the ADE and anterior embryonic
CC       mesoderm. At 8.5 dpc, expressed more broadly in anterior tissues and at
CC       the midline of the neural plate in the midbrain region as well as the
CC       lateral margins of the neural plate posterior to the metencephalic
CC       region. Also weakly expressed in the anterior mesenchyme. At 9.5 dpc,
CC       strongest expression in branchial arches and limb buds. During mid-
CC       gestation, expression continues in mesenchymal cells, particularly in
CC       areas where these cells condense. {ECO:0000269|PubMed:19097194,
CC       ECO:0000269|PubMed:19465597}.
CC   -!- DEVELOPMENTAL STAGE: Expressed throughout embryogenesis and in
CC       adulthood. During embryogenesis, expression is high at transition
CC       phases of mesenchymal cell differentiation such as from mesenchymal
CC       cells to chondrocytes and from mesenchymal to mesothelial cells.
CC       Expressed throughout all stages of humerus bone formation. During lung
CC       development, expressed in all mesenchymal cells at the early
CC       pseudoglandular stage. Expression is rapidly lost from the mesenchyme
CC       of the lung interstitium during the mid-to-late pseudoglandular stage
CC       but continues throughout life in the mesothelial pleural cells.
CC       {ECO:0000269|PubMed:19097194, ECO:0000269|PubMed:19465597}.
CC   -!- INDUCTION: Down-regulated by hedgehog (Hh) signaling.
CC       {ECO:0000269|PubMed:23792766}.
CC   -!- PTM: Phosphorylated on tyrosines; probably via autophosphorylation.
CC       {ECO:0000269|PubMed:25171405}.
CC   -!- PTM: N-glycosylated. {ECO:0000269|PubMed:25171405}.
CC   -!- DISRUPTION PHENOTYPE: Morphological defects at birth including growth
CC       retardation, short limbs, cleft palate, sternal dysraphia, shortened
CC       intestine and cyanosis. Long bones display reduced mineralization due
CC       to delayed chondrocyte differentiation. Neonates breathe abnormally, do
CC       not suckle and die within a day after birth, probably due to
CC       insufficient respiration as a result of the cleft palate.
CC       {ECO:0000269|PubMed:19097194, ECO:0000269|PubMed:19465597}.
CC   -!- SIMILARITY: Belongs to the protein kinase superfamily. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH86639.1; Type=Frameshift; Evidence={ECO:0000305};
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DR   EMBL; AB436780; BAG82823.1; -; mRNA.
DR   EMBL; AB381893; BAH66379.1; -; mRNA.
DR   EMBL; BC022157; AAH22157.1; -; mRNA.
DR   EMBL; BC086639; AAH86639.1; ALT_FRAME; mRNA.
DR   EMBL; AK133913; BAE21924.1; -; mRNA.
DR   CCDS; CCDS28994.2; -. [Q5RJI4-1]
DR   RefSeq; NP_598878.2; NM_134117.2. [Q5RJI4-1]
DR   RefSeq; XP_011244536.1; XM_011246234.1.
DR   AlphaFoldDB; Q5RJI4; -.
DR   SMR; Q5RJI4; -.
DR   STRING; 10090.ENSMUSP00000129238; -.
DR   GlyCosmos; Q5RJI4; 5 sites, No reported glycans.
DR   GlyGen; Q5RJI4; 5 sites.
DR   iPTMnet; Q5RJI4; -.
DR   PhosphoSitePlus; Q5RJI4; -.
DR   PaxDb; 10090-ENSMUSP00000129238; -.
DR   ProteomicsDB; 289602; -. [Q5RJI4-1]
DR   ProteomicsDB; 289603; -. [Q5RJI4-2]
DR   Antibodypedia; 29709; 70 antibodies from 21 providers.
DR   Ensembl; ENSMUST00000170794.8; ENSMUSP00000129238.2; ENSMUSG00000024247.15. [Q5RJI4-1]
DR   GeneID; 106522; -.
DR   KEGG; mmu:106522; -.
DR   UCSC; uc012axu.1; mouse. [Q5RJI4-1]
DR   AGR; MGI:2147077; -.
DR   CTD; 91461; -.
DR   MGI; MGI:2147077; Pkdcc.
DR   VEuPathDB; HostDB:ENSMUSG00000024247; -.
DR   eggNOG; KOG1187; Eukaryota.
DR   GeneTree; ENSGT00390000001205; -.
DR   HOGENOM; CLU_044025_1_0_1; -.
DR   InParanoid; Q5RJI4; -.
DR   OMA; HEGCLLS; -.
DR   OrthoDB; 5392475at2759; -.
DR   PhylomeDB; Q5RJI4; -.
DR   TreeFam; TF329248; -.
DR   BioGRID-ORCS; 106522; 3 hits in 80 CRISPR screens.
DR   ChiTaRS; Pkdcc; mouse.
DR   PRO; PR:Q5RJI4; -.
DR   Proteomes; UP000000589; Chromosome 17.
DR   RNAct; Q5RJI4; Protein.
DR   Bgee; ENSMUSG00000024247; Expressed in internal carotid artery and 246 other cell types or tissues.
DR   ExpressionAtlas; Q5RJI4; baseline and differential.
DR   GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR   GO; GO:0005794; C:Golgi apparatus; IDA: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; IDA:UniProtKB.
DR   GO; GO:0030282; P:bone mineralization; IMP:MGI.
DR   GO; GO:0030154; P:cell differentiation; IEA:UniProtKB-KW.
DR   GO; GO:0048566; P:embryonic digestive tract development; IMP:UniProtKB.
DR   GO; GO:0035108; P:limb morphogenesis; IMP:MGI.
DR   GO; GO:0048286; P:lung alveolus development; IMP:UniProtKB.
DR   GO; GO:0035264; P:multicellular organism growth; IMP:MGI.
DR   GO; GO:0042997; P:negative regulation of Golgi to plasma membrane protein transport; IDA:UniProtKB.
DR   GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR   GO; GO:0030501; P:positive regulation of bone mineralization; IMP:UniProtKB.
DR   GO; GO:0032332; P:positive regulation of chondrocyte differentiation; IMP:UniProtKB.
DR   GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR   GO; GO:0060021; P:roof of mouth development; IMP:UniProtKB.
DR   GO; GO:0001501; P:skeletal system development; IMP:MGI.
DR   Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1.
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:SF3; EXTRACELLULAR TYROSINE-PROTEIN KINASE PKDCC; 1.
DR   PANTHER; PTHR46448; PROTEIN KINASE DOMAIN-CONTAINING PROTEIN; 1.
DR   Pfam; PF12260; PIP49_C; 1.
DR   SUPFAM; SSF56112; Protein kinase-like (PK-like); 1.
DR   PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR   Genevisible; Q5RJI4; MM.
PE   1: Evidence at protein level;
KW   Alternative splicing; ATP-binding; Developmental protein; Differentiation;
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..492
FT                   /note="Extracellular tyrosine-protein kinase PKDCC"
FT                   /id="PRO_0000263011"
FT   DOMAIN          138..422
FT                   /note="Protein kinase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT   REGION          29..130
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        54..69
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        96..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:0000269|PubMed:19465597"
FT   MOD_RES         177
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000269|PubMed:19465597"
FT   CARBOHYD        137
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT   CARBOHYD        320
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT   CARBOHYD        369
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT   CARBOHYD        400
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT   CARBOHYD        459
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT   VAR_SEQ         72..118
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_038822"
FT   MUTAGEN         148
FT                   /note="Y->F: Does not affect kinase activity nor secretion
FT                   to the extracellular medium."
FT                   /evidence="ECO:0000269|PubMed:25171405"
FT   MUTAGEN         166
FT                   /note="K->M: Complete loss of kinase activity.
FT                   Phosphorylation is restored by co-transfection with
FT                   wild-type protein."
FT                   /evidence="ECO:0000269|PubMed:19465597,
FT                   ECO:0000269|PubMed:25171405"
FT   MUTAGEN         199
FT                   /note="E->A: Complete loss of kinase activity."
FT                   /evidence="ECO:0000269|PubMed:25171405"
FT   MUTAGEN         295
FT                   /note="D->A: Complete loss of kinase activity."
FT                   /evidence="ECO:0000269|PubMed:25171405"
SQ   SEQUENCE   492 AA;  53841 MW;  AD95CAF730625FF9 CRC64;
     MRRRRAAVAA GFCASFLLGS VLNVLFAPGS EPPRPGQSPG SSAAPGPGRR GGRGELARQI
     RERYEEVQRY SRGGPGPGAG RPERRRLMDL APGGPGLQRP RPPRVRSPPD GAPGWPPAPG
     PGSPGPGPRL GCAALRNVSG AQYVGSGYTK AVYRVRLPGG AAVALKAVDF SGHDLGSCVR
     EFGARRGCYR LAAHKLLKEM VLLERLRHPN VLQLYGYCYQ DSEGIPDTLT TITELGAPVE
     MIQLLQTSWE DRFRICLSLG RLLHHLAHSP LGSVTLLDFR PRQFVLVNGE LKVTDLDDAR
     VEETPCTSSA DCTLEFPARN FSLPCSAQGW CEGMNEKRNL YNAYRFFFTY LLPHSAPPSL
     RPLLDSIVNA TGELAWGVDE TLAQLETALH LFRSGQYLQN STSSRAEYQR IPDSAITQED
     YRCWPSYHHG GCLLSVFNLA EAIDVCESHA QCRAFVVTNQ TTWTGRKLVF FKTGWNQVVP
     DAGKTTYVKA PG
//