Q62101 (KPCD1_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified July 9, 2014. Version 139. History...
Names and origin
|Protein names||Recommended name:|
Serine/threonine-protein kinase D1
Protein kinase C mu type
Protein kinase D
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||918 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of MAPK8/JNK1 and Ras signaling, Golgi membrane integrity and trafficking, cell survival through NF-kappa-B activation, cell migration, cell differentiation by mediating HDAC7 nuclear export, cell proliferation via MAPK1/3 (ERK1/2) signaling, and plays a role in cardiac hypertrophy, VEGFA-induced angiogenesis, genotoxic-induced apoptosis and flagellin-stimulated inflammatory response. Phosphorylates the epidermal growth factor receptor (EGFR) on dual threonine residues, which leads to the suppression of epidermal growth factor (EGF)-induced MAPK8/JNK1 activation and subsequent JUN phosphorylation. Phosphorylates RIN1, inducing RIN1 binding to 14-3-3 proteins YWHAB, YWHAE and YWHAZ and increased competition with RAF1 for binding to GTP-bound form of Ras proteins (NRAS, HRAS and KRAS). Acts downstream of the heterotrimeric G-protein beta/gamma-subunit complex to maintain the structural integrity of the Golgi membranes, and is required for protein transport along the secretory pathway. In the trans-Golgi network (TGN), regulates the fission of transport vesicles that are on their way to the plasma membrane. May act by activating the lipid kinase phosphatidylinositol 4-kinase beta (PI4KB) at the TGN for the local synthesis of phosphorylated inositol lipids, which induces a sequential production of DAG, phosphatidic acid (PA) and lyso-PA (LPA) that are necessary for membrane fission and generation of specific transport carriers to the cell surface. Under oxidative stress, is phosphorylated at Tyr-469 via SRC-ABL1 and contributes to cell survival by activating IKK complex and subsequent nuclear translocation and activation of NFKB1. Involved in cell migration by regulating integrin alpha-5/beta-3 recycling and promoting its recruitment in newly forming focal adhesion. In osteoblast differentiation, mediates the bone morphogenic protein 2 (BMP2)-induced nuclear export of HDAC7, which results in the inhibition of HDAC7 transcriptional repression of RUNX2. In neurons, plays an important role in neuronal polarity by regulating the biogenesis of TGN-derived dendritic vesicles, and is involved in the maintenance of dendritic arborization and Golgi structure in hippocampal cells. May potentiate mitogenesis induced by the neuropeptide bombesin or vasopressin by mediating an increase in the duration of MAPK1/3 (ERK1/2) signaling, which leads to accumulation of immediate-early gene products including FOS that stimulate cell cycle progression. Plays an important role in the proliferative response induced by low calcium in keratinocytes, through sustained activation of MAPK1/3 (ERK1/2) pathway. Downstream of novel PKC signaling, plays a role in cardiac hypertrophy by phosphorylating HDAC5, which in turn triggers XPO1/CRM1-dependent nuclear export of HDAC5, MEF2A transcriptional activation and induction of downstream target genes that promote myocyte hypertrophy and pathological cardiac remodeling. Mediates cardiac troponin I (TNNI3) phosphorylation at the PKA sites, which results in reduced myofilament calcium sensitivity, and accelerated crossbridge cycling kinetics. The PRKD1-HDAC5 pathway is also involved in angiogenesis by mediating VEGFA-induced specific subset of gene expression, cell migration, and tube formation. In response to VEGFA, is necessary and required for HDAC7 phosphorylation which induces HDAC7 nuclear export and endothelial cell proliferation and migration. During apoptosis induced by cytarabine and other genotoxic agents, PRKD1 is cleaved by caspase-3 at Asp-378, resulting in activation of its kinase function and increased sensitivity of cells to the cytotoxic effects of genotoxic agents. In epithelial cells, is required for transducing flagellin-stimulated inflammatory responses by binding and phosphorylating TLR5, which contributes to MAPK14/p38 activation and production of inflammatory cytokines. May play a role in inflammatory response by mediating activation of NF-kappa-B. May be involved in pain transmission by directly modulating TRPV1 receptor. Ref.4 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11
ATP + a protein = ADP + a phosphoprotein.
Activated by DAG and phorbol esters. Phorbol-ester/DAG-type domain 1 binds DAG with high affinity and appears to play the dominant role in mediating translocation to the cell membrane and trans-Golgi network. Phorbol-ester/DAG-type domain 2 binds phorbol ester with higher affinity. Autophosphorylation of Ser-748 and phosphorylation of Ser-744 by PKC relieves auto-inhibition by the PH domain. Phosphorylation on Tyr-469 by the SRC-ABL1 pathway in response to oxidative stress, is also required for activation. Activated by DAPK1 under oxidative stress By similarity. Ref.7
Interacts (via N-terminus) with ADAP1/CENTA1. Interacts with MAPK13 and SRC By similarity. Interacts with DAPK1 in an oxidative stress-regulated manner By similarity.
Phosphorylated at Ser-403 and Ser-407 by MAPK13 during regulation of insulin secretion in pancreatic beta cells. Phosphorylated by DAPK1. Phosphorylated by ABL at Tyr-469, which primes the kinase in response to oxidative stress, and promotes a second step activating phosphorylation at Ser-744/Ser-748 by PKRD By similarity. Ref.3 Ref.5 Ref.7
Contains 1 PH domain.
Contains 2 phorbol-ester/DAG-type zinc fingers.
Contains 1 protein kinase domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 918||918||Serine/threonine-protein kinase D1||PRO_0000055715|
|Domain||428 – 547||120||PH|
|Domain||589 – 845||257||Protein kinase|
|Zinc finger||144 – 194||51||Phorbol-ester/DAG-type 1|
|Zinc finger||276 – 326||51||Phorbol-ester/DAG-type 2|
|Nucleotide binding||595 – 603||9||ATP By similarity|
|Compositional bias||16 – 26||11||Poly-Ala|
|Compositional bias||198 – 201||4||Poly-Arg|
|Active site||712||1||Proton acceptor By similarity|
|Binding site||618||1||ATP By similarity|
Amino acid modifications
|Modified residue||93||1||Phosphotyrosine By similarity|
|Modified residue||203||1||Phosphoserine By similarity|
|Modified residue||206||1||Phosphoserine By similarity|
|Modified residue||351||1||Phosphoserine By similarity|
|Modified residue||403||1||Phosphoserine; by MAPK13 By similarity|
|Modified residue||407||1||Phosphoserine; by MAPK13 By similarity|
|Modified residue||438||1||Phosphotyrosine By similarity|
|Modified residue||454||1||Phosphoserine By similarity|
|Modified residue||469||1||Phosphotyrosine; by ABL By similarity|
|Modified residue||508||1||Phosphotyrosine By similarity|
|Modified residue||744||1||Phosphoserine; by PKC/PRKCD Ref.5 Ref.7|
|Modified residue||748||1||Phosphoserine; by autocatalysis and PKC/PRKCD Ref.5 Ref.7|
|Modified residue||916||1||Phosphoserine; by autocatalysis Ref.3|
|Mutagenesis||744||1||S → A: Loss of basal kinase activity and phorbol ester-stimulated kinase activity; when associated with A-748. Ref.7|
|Mutagenesis||744||1||S → D: High basal kinase activity, loss of phorbol ester-stimulated kinase activity; when associated with D-748. Ref.7|
|Mutagenesis||748||1||S → A: Loss of basal kinase activity and phorbol ester-stimulated kinase activity; when associated with A-744. Ref.7|
|Mutagenesis||748||1||S → D: High basal kinase activity, loss of phorbol ester-stimulated kinase activity; when associated with D-744. Ref.7|
|Sequence conflict||683||1||R → W in CAA84283. Ref.1|
|||"Molecular cloning and characterization of protein kinase D: a target for diacylglycerol and phorbol esters with a distinctive catalytic domain."|
Valverde A.M., Sinnet-Smith J., Van Lint J., Rozengurt E.
Proc. Natl. Acad. Sci. U.S.A. 91:8572-8576(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"Lineage-specific biology revealed by a finished genome assembly of the mouse."|
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
|||"Characterization of serine 916 as an in vivo autophosphorylation site for protein kinase D/protein kinase Cmu."|
Matthews S.A., Rozengurt E., Cantrell D.
J. Biol. Chem. 274:26543-26549(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-916.
|||"Protein kinase D regulates the fission of cell surface destined transport carriers from the trans-Golgi network."|
Liljedahl M., Maeda Y., Colanzi A., Ayala I., Van Lint J., Malhotra V.
Cell 104:409-420(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN REGULATION OF TRANS-GOLGI NETWORK, SUBCELLULAR LOCATION.
|||"Activation loop Ser744 and Ser748 in protein kinase D are transphosphorylated in vivo."|
Waldron R.T., Rey O., Iglesias T., Tugal T., Cantrell D., Rozengurt E.
J. Biol. Chem. 276:32606-32615(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-744 AND SER-748.
|||"The RAS effector RIN1 directly competes with RAF and is regulated by 14-3-3 proteins."|
Wang Y., Waldron R.T., Dhaka A., Patel A., Riley M.M., Rozengurt E., Colicelli J.
Mol. Cell. Biol. 22:916-926(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN RIN1 PHOSPHORYLATION.
|||"Protein kinase C phosphorylates protein kinase D activation loop Ser744 and Ser748 and releases autoinhibition by the pleckstrin homology domain."|
Waldron R.T., Rozengurt E.
J. Biol. Chem. 278:154-163(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, MUTAGENESIS OF SER-744 AND SER-748, PHOSPHORYLATION AT SER-744 AND SER-748.
|||"PKD1/PKCmu promotes alphavbeta3 integrin recycling and delivery to nascent focal adhesions."|
Woods A.J., White D.P., Caswell P.T., Norman J.C.
EMBO J. 23:2531-2543(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL MIGRATION.
|||"Protein kinase D potentiates DNA synthesis induced by Gq-coupled receptors by increasing the duration of ERK signaling in swiss 3T3 cells."|
Sinnett-Smith J., Zhukova E., Hsieh N., Jiang X., Rozengurt E.
J. Biol. Chem. 279:16883-16893(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL PROLIFERATION.
|||"Bone morphogenic protein 2 activates protein kinase D to regulate histone deacetylase 7 localization and repression of Runx2."|
Jensen E.D., Gopalakrishnan R., Westendorf J.J.
J. Biol. Chem. 284:2225-2234(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN OSTEOBLAST DIFFERENTIATION.
|||"Protein kinase D is implicated in the reversible commitment to differentiation in primary cultures of mouse keratinocytes."|
Jadali A., Ghazizadeh S.
J. Biol. Chem. 285:23387-23397(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL PROLIFERATION.
|+||Additional computationally mapped references.|
|Z34524 mRNA. Translation: CAA84283.1.|
AC099603 Genomic DNA. No translation available.
AC154543 Genomic DNA. No translation available.
CT009740 Genomic DNA. No translation available.
CT010578 Genomic DNA. No translation available.
|RefSeq||NP_032884.2. NM_008858.3. |
3D structure databases
|SMR||Q62101. Positions 145-194, 277-326, 426-547, 556-847. |
Protein-protein interaction databases
|IntAct||Q62101. 2 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000002765; ENSMUSP00000002765; ENSMUSG00000002688. |
|UCSC||uc007nmj.1. mouse. |
|MGI||MGI:99879. Prkd1. |
Enzyme and pathway databases
|BRENDA||220.127.116.11. 3474. |
Gene expression databases
Family and domain databases
|Gene3D||18.104.22.168. 1 hit. |
|InterPro||IPR020454. DAG/PE-bd. |
|PANTHER||PTHR22968. PTHR22968. 1 hit. |
|Pfam||PF00130. C1_1. 2 hits. |
PF00169. PH. 1 hit.
PF00069. Pkinase. 1 hit.
|PIRSF||PIRSF000552. PKC_mu_nu_D2. 1 hit. |
|PRINTS||PR00008. DAGPEDOMAIN. |
|SMART||SM00109. C1. 2 hits. |
SM00233. PH. 1 hit.
SM00220. S_TKc. 1 hit.
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|PROSITE||PS50003. PH_DOMAIN. 1 hit. |
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS00479. ZF_DAG_PE_1. 2 hits.
PS50081. ZF_DAG_PE_2. 2 hits.
|Accession||Primary (citable) accession number: Q62101|
Secondary accession number(s): E9QNA3
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|