InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: PRKD1

Summary

InnateDB Protein

IDBP-4217.5

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

PRKD1

Protein Name

protein kinase D1

Synonyms

PKC-MU; PKCM; PKD; PRKCM;

Species

Homo sapiens

Ensembl Protein

ENSP00000333568

InnateDB Gene

IDBG-4215 (PRKD1)

Protein Structure

UniProt Annotation

Function

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-463 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. {ECO:0000269PubMed:10523301, ECO:0000269PubMed:10764790, ECO:0000269PubMed:12505989, ECO:0000269PubMed:12637538, ECO:0000269PubMed:15471852, ECO:0000269PubMed:17442957, ECO:0000269PubMed:18332134, ECO:0000269PubMed:18509061, ECO:0000269PubMed:19135240, ECO:0000269PubMed:19211839}.

Subcellular Localization

Cytoplasm {ECO:0000269PubMed:18076381}. Cell membrane {ECO:0000269PubMed:18076381}. Golgi apparatus, trans-Golgi network {ECO:0000250}. Note=Translocation to the cell membrane is required for kinase activation.

Disease Associations

Tissue Specificity

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 48 experimentally validated interaction(s) in this database.

Experimentally validated
Total	48 [view]
Protein-Protein	48 [view]
Protein-DNA	0
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004674	protein serine/threonine kinase activity
GO:0004697	protein kinase C activity
GO:0004713	protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0042802	identical protein binding
GO:0046872	metal ion binding

Biological Process

GO:0001525	angiogenesis
GO:0001938	positive regulation of endothelial cell proliferation
GO:0006468	protein phosphorylation
GO:0006665	sphingolipid metabolic process
GO:0006915	apoptotic process
GO:0006954	inflammatory response
GO:0007030	Golgi organization
GO:0007165	signal transduction
GO:0007229	integrin-mediated signaling pathway
GO:0008283	cell proliferation
GO:0010595	positive regulation of endothelial cell migration
GO:0010837	regulation of keratinocyte proliferation
GO:0010976	positive regulation of neuron projection development
GO:0018105	peptidyl-serine phosphorylation
GO:0030148	sphingolipid biosynthetic process
GO:0032793	positive regulation of CREB transcription factor activity
GO:0033138	positive regulation of peptidyl-serine phosphorylation
GO:0034599	cellular response to oxidative stress
GO:0035556	intracellular signal transduction
GO:0035924	cellular response to vascular endothelial growth factor stimulus
GO:0038033	positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway
GO:0043123	positive regulation of I-kappaB kinase/NF-kappaB signaling
GO:0043536	positive regulation of blood vessel endothelial cell migration
GO:0044281	small molecule metabolic process
GO:0045087	innate immune response
GO:0045669	positive regulation of osteoblast differentiation
GO:0045766	positive regulation of angiogenesis
GO:0045806	negative regulation of endocytosis
GO:0045944	positive regulation of transcription from RNA polymerase II promoter
GO:0046777	protein autophosphorylation
GO:0048010	vascular endothelial growth factor receptor signaling pathway
GO:0048193	Golgi vesicle transport
GO:0051092	positive regulation of NF-kappaB transcription factor activity
GO:0060548	negative regulation of cell death
GO:1901727	positive regulation of histone deacetylase activity
GO:2001028	positive regulation of endothelial cell chemotaxis
GO:2001044	regulation of integrin-mediated signaling pathway

Cellular Component

GO:0005634	nucleus
GO:0005737	cytoplasm
GO:0005802	trans-Golgi network
GO:0005829	cytosol
GO:0005886	plasma membrane
GO:0005887	integral component of plasma membrane
GO:0005911	cell-cell junction
GO:0005938	cell cortex

Protein Structure and Domains

PDB ID

InterPro

IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR001849 Pleckstrin homology domain
IPR002219 Protein kinase C-like, phorbol ester/diacylglycerol-binding domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR011009 Protein kinase-like domain
IPR020454 Diacylglycerol/phorbol-ester binding
IPR020635 Tyrosine-protein kinase, catalytic domain

PFAM

PF00069
PF07714
PF00169
PF00130

PRINTS

PR00109
PR00008

PIRSF

SMART

SM00233
SM00109
SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt