PRKD1
PRKD1 is a serine/threonine protein kinase involved in many cellular processes, including Golgi body membrane integrity and transport, cell migration and differentiation, MAPK8/JNK1 and Ras pathway signaling, MAPK1/3 (ERK1/2) pathway signaling, cell survival, and regulation of cell shape and adhesion.
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 morphogenetic 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. Plays a role in activated KRAS-mediated stabilization of ZNF304 in colorectal cancer (CRC) cells (PubMed:24623306).
Regulates nuclear translocation of transcription factor TFEB in macrophages upon live S.enterica infection (By similarity).
Biological Process
AngiogenesisIEA:UniProtKB-KW
Apoptotic processIEA:UniProtKB-KW
Cell differentiationIEA:UniProtKB-KW
Cellular response to amino acid starvationManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Cellular response to hydroperoxideManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Cellular response to oxidative stressManual Assertion Based On ExperimentIDA:UniProtKB
Cellular response to vascular endothelial growth factor stimulusManual Assertion Based On ExperimentIMP:UniProtKB
Defense response to Gram-negative bacteriumIEA:Ensembl
Golgi organizationManual Assertion Based On ExperimentIMP:UniProtKB
Golgi vesicle transportISS:UniProtKB
Inflammatory responseIEA:UniProtKB-KW
Innate immune responseIEA:UniProtKB-KW
Integrin-mediated signaling pathwayManual Assertion Based On ExperimentTAS:BHF-UCL
Intracellular signal transductionManual Assertion Based On ExperimentIMP:BHF-UCL
Negative regulation of cell deathManual Assertion Based On ExperimentIMP:UniProtKB
Negative regulation of endocytosisManual Assertion Based On ExperimentTAS:BHF-UCL
Nervous system developmentIEA:UniProtKB-KW
Peptidyl-serine phosphorylationManual Assertion Based On ExperimentIDA:BHF-UCL
Peptidyl-threonine phosphorylationManual Assertion Based On ExperimentIDA:ParkinsonsUK-UCL
Positive regulation of angiogenesisManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of autophagyManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Positive regulation of blood vessel endothelial cell migrationManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of CREB transcription factor activityManual Assertion Based On ExperimentIGI:BHF-UCL
Positive regulation of endothelial cell chemotaxisManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of endothelial cell migrationManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of endothelial cell proliferationManual Assertion Based On ExperimentIGI:BHF-UCL
Positive regulation of histone deacetylase activityManual Assertion Based On ExperimentIGI:BHF-UCL
Positive regulation of I-kappaB kinase/NF-kappaB signalingManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of neuron projection developmentManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of NF-kappaB transcription factor activityManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of osteoblast differentiationISS:UniProtKB
Positive regulation of peptidyl-serine phosphorylationManual Assertion Based On ExperimentIGI:BHF-UCL
Positive regulation of phosphatidylinositol 3-kinase activity1 PublicationIC:ParkinsonsUK-UCL
Positive regulation of protein import into nucleusIEA:Ensembl
Positive regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIMP:BHF-UCL
Protein autophosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Protein kinase D signalingManual Assertion Based On ExperimentIGI:BHF-UCL
Protein phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Ras protein signal transductionManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of integrin-mediated signaling pathwayManual Assertion Based On ExperimentTAS:BHF-UCL
Regulation of keratinocyte proliferationISS:UniProtKB
Regulation of protein stabilityManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of release of sequestered calcium ion into cytosolIEA:Ensembl
Signal transductionManual Assertion Based On ExperimentTAS:ProtInc
Sphingolipid biosynthetic processTAS:Reactome
Vascular endothelial growth factor receptor signaling pathwayManual Assertion Based On ExperimentIMP:BHF-UCL
Involvement in disease
Congenital heart defects and ectodermal dysplasia (CHDED):
An autosomal dominant syndrome characterized by atrial and/or ventricular septal congenital heart defects and variable features of ectodermal dysplasia, including sparse hair, dry skin, thin skin, fragile nails, premature loss of primary teeth, and small widely spaced teeth. Patients manifest developmental disabilities ranging from motor delay and delayed speech to global developmental retardation.
PTM
Phosphorylated at Ser-397 and Ser-401 by MAPK13 during regulation of insulin secretion in pancreatic beta cells (PubMed:19135240).
Phosphorylated by DAPK1 (PubMed:17703233).
Phosphorylated at Tyr-95 and by ABL at Tyr-463, which primes the kinase in response to oxidative stress, and promotes a second step activating phosphorylation at Ser-738/Ser-742 by PKRD (PubMed:12637538, PubMed:15024053, PubMed:17804414).
Phosphorylated on Ser-910 upon S.enterica infection in macrophages (By similarity).
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Datasheet