Affinage

PRKD3

Serine/threonine-protein kinase D3 · UniProt O94806

Length
890 aa
Mass
100.5 kDa
Annotated
2026-06-10
31 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRKD3 (PKD3) is a diacylglycerol/phorbol ester-responsive serine-threonine kinase that acts as a downstream effector of protein kinase C to couple receptor and lipid signaling to proliferation, survival, metabolism, and invasion across multiple tissues (PMID:18483269, PMID:19028687, PMID:15927450). Its C1a domain mediates high-affinity phorbol ester binding, and both C1a and intrinsic kinase activity are required for PMA-induced plasma-membrane translocation, with PKC directly activating PKD3 to control its localization (PMID:15927450); activation downstream of PKC (and, in cardiomyocytes, Rho) is broadly elicited by hormonal, cholinergic, and growth-factor stimuli (PMID:19028687, PMID:27515283, PMID:20621130). Once activated, PKD3 drives a pro-invasive transcriptional program by phosphorylating p65 NF-κB on Ser536 and suppressing HDAC1 to de-repress uPA, and it directly phosphorylates GIT1 on Ser46 to shift GIT1 between focal adhesions and motile paxillin-positive complexes, linking the kinase to focal-adhesion dynamics and cell motility (PMID:22797919, PMID:22893698). PKD3 also governs lipid and glucose metabolism: it interacts with SREBP1 to promote its maturation and FASN-driven lipogenesis in prostate cancer, and in hepatocytes it is the predominant isoform, exerting negative feedback on AKT/mTORC1/mTORC2 insulin signaling while activating PKA-mediated glucose and tyrosine metabolism (PMID:31387939, PMID:31772672, PMID:34145024). In cancer, PKD3 supports mTORC1/mTORC2 signaling at endolysosomal membranes, localizes to Rab7-positive late endosomes to sustain retromer recruitment and endosomal acidification, and maintains triple-negative breast cancer and multiple myeloma stem/tumor-initiating populations, in part through an IRF4 feed-forward circuit and Hsp90-dependent stabilization (PMID:24337579, PMID:31745977, PMID:36672148, PMID:41655233, PMID:40970203).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2005 High

    Established the structural basis for PKD3 membrane recruitment, answering how the kinase senses lipid second messengers and is positioned at the plasma membrane.

    Evidence Radioligand binding with C1a/C1b mutants and live-cell imaging of GFP-PKD3 with PKC inhibition

    PMID:15927450

    Open questions at the time
    • Does not define which substrates are phosphorylated at the membrane
    • Structural model of the activated kinase not resolved
  2. 2008 Medium

    Defined PKD3 as a pro-growth, pro-survival effector in a PKCε/PKD3 axis, framing its role in cell-cycle progression and apoptosis resistance.

    Evidence Overexpression/siRNA in prostate cancer cells with cell-cycle, kinase-activity, and ERK/Akt readouts

    PMID:18483269 PMID:19028687

    Open questions at the time
    • Direct nuclear substrates not identified
    • Mechanism of nuclear localization control unresolved
  3. 2012 High

    Identified two direct mechanistic outputs of PKD3 — transcriptional de-repression of uPA via p65/HDAC1 and a direct GIT1-S46 phosphorylation switch — connecting the kinase to invasion and focal-adhesion dynamics.

    Evidence Reciprocal Co-IP, ChIP, epistatic rescue, and MS-based substrate identification with phosphomimetic mutants

    PMID:22797919 PMID:22893698

    Open questions at the time
    • Whether p65-S536 is a direct PKD3 substrate vs. indirect not fully separated
    • GIT1-S46 switch not validated in vivo
  4. 2013 Medium

    Placed PKD3 upstream of mTORC1 at endolysosomal membranes, linking it to autophagy and lysosomal homeostasis in TNBC.

    Evidence Antibody array, siRNA knockdown, and immunofluorescence for endolysosomal/LC3 markers

    PMID:24337579

    Open questions at the time
    • Direct mTORC1-pathway substrate of PKD3 not identified
    • Mechanism of endolysosomal recruitment unresolved
  5. 2019 High

    Revealed PKD3 as a tissue-specific metabolic regulator and a lipogenesis driver, showing context-dependent suppression of insulin signaling in liver versus SREBP1-driven lipogenesis in cancer.

    Evidence Hepatic knockout/constitutively-active mouse models with metabolic readouts, and Co-IP/ChIP/rescue for SREBP1-FASN in prostate cancer

    PMID:31387939 PMID:31745977 PMID:31772672

    Open questions at the time
    • Direct PKD3 phosphorylation sites on insulin-pathway components not mapped
    • Reconciliation of pro- vs anti-mTOR roles across tissues incomplete
  6. 2021 Medium

    Expanded PKD3 regulatory inputs and outputs, identifying TRIM47-mediated kinase stabilization and a glucagon/PKA metabolic branch with a large putative substrate set.

    Evidence Co-IP, ubiquitination assays in breast cancer cells, and phosphoproteomics with PKA biochemical validation in hepatocytes

    PMID:34145024 PMID:34433666

    Open questions at the time
    • Most of the >300 putative substrates not individually validated
    • Direct vs PKA-mediated phosphorylation events not distinguished
  7. 2023 Medium

    Established PKD3 as an Hsp90 client whose stability is chaperone-dependent, identifying a druggable vulnerability for PKD3-driven migration.

    Evidence PLA, reciprocal Co-IP, Hsp90 inhibition with proteasome-rescue in prostate cancer cells

    PMID:36672148

    Open questions at the time
    • Hsp90 co-chaperone requirements not defined
    • Effect on other PKD3 functions beyond migration untested
  8. 2025 Medium

    Resolved an endosomal function for endogenous PKD3 at Rab7-positive late endosomes governing retromer recruitment, acidification, and stemness, anchoring earlier endolysosomal phenotypes to a defined compartment.

    Evidence Endogenous immunofluorescence localization plus retromer, cathepsin D secretion, endosomal pH, and Wnt/stemness assays in TNBC

    PMID:40970203

    Open questions at the time
    • Endosomal PKD3 substrates not identified
    • Mechanism coupling PKD3 to retromer recruitment unknown
  9. 2026 Medium

    Defined a kinase-activity-independent scaffolding role for PKD3 in an mTOR/IRF4 feed-forward circuit sustaining multiple myeloma, showing PKD3 functions extend beyond catalysis.

    Evidence Co-IP with mTOR, kinase-dead mutant analysis, ChIP-seq/luciferase, and xenograft models

    PMID:41655233

    Open questions at the time
    • How activation-loop phosphorylation enables kinase-independent function unclear
    • Direct PKD3-mTOR binding interface not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The unifying logic that determines which PKD3 outputs (transcriptional, metabolic, endosomal, scaffolding) dominate in a given cell type, and the full direct substrate repertoire, remains unresolved.
  • No comprehensive validated direct substrate map
  • Context-dependent compartment selection mechanism unknown
  • No structural model of activated full-length PKD3

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 3 GO:0016740 transferase activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0008289 lipid binding 1
Localization
GO:0005634 nucleus 2 GO:0005768 endosome 2 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
GIT1HDAC1HSP90IKKΒMTORPKCΕSREBP1TRIM47
Complex memberships
TRIM47-PKCε-PKD3 complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 PKD3 promotes prostate cancer cell growth and survival through a PKCε/PKD3 pathway downstream of Akt and ERK1/2. PKCε regulates PKD3 kinase activity and nuclear localization in PC3 and DU145 cells. Overexpression of PKD3 blocks PMA-induced apoptosis, prolonged ERK1/2 activation, and promotes S phase entry; depletion causes G0-G1 arrest. PKD3-mediated Akt upregulation requires PI3K and p38. Overexpression and siRNA knockdown of PKD3, cell cycle analysis, kinase activity assays, Western blotting for Akt and ERK1/2, immunohistochemistry for subcellular localization Cancer research Medium 18483269
2012 PKD3 promotes prostate cancer cell invasion by phosphorylating Ser536 on p65 NF-κB, thereby activating uPA transcription. PKD3 also interacts with and suppresses HDAC1, reducing HDAC1 binding to the uPA promoter and thus de-repressing uPA expression. PKD3 interacts physically with IKKβ. siRNA knockdown of PKD2/PKD3, Co-IP (PKD3–IKKβ and PKD3–HDAC1 interactions), ChIP for p65 binding to uPA promoter, rescue experiments with constitutive Ser536 p65 and p65 overexpression, invasion/migration assays Journal of cell science High 22797919
2021 TRIM47 forms a ternary complex with PKCε and PKD3, stabilizing both kinases. TRIM47 promotes lysine-27-linked polyubiquitination of PKCε, and this complex activates NF-κB signaling to drive breast cancer proliferation and endocrine therapy resistance. Co-immunoprecipitation (TRIM47–PKCε–PKD3 complex), ubiquitination assays, overexpression and siRNA knockdown in MCF-7 and OHTR cells, proliferation assays Proceedings of the National Academy of Sciences of the United States of America Medium 34433666
2013 PKD3 activates S6K1 (a downstream target of mTORC1) in triple-negative breast cancer cells. PKD3 knockdown reduces S6K1 phosphorylation, impairs mTORC1 activation at endolysosomal membranes, causes accumulation of mannose-6-phosphate receptor, and recruits the autophagy marker LC3 to enlarged acidic vesicles. Antibody array, siRNA knockdown, Western blotting for S6K1 phosphorylation, immunofluorescence for endolysosomal markers and LC3 The Journal of biological chemistry Medium 24337579
2012 PKD3 directly phosphorylates GIT1 on serine 46. This phosphorylation acts as a molecular switch that shifts GIT1 localization from focal adhesions to motile, paxillin-positive cytoplasmic complexes, thereby regulating paxillin trafficking and cellular protrusive activity. Mass spectrometry-based phosphoproteomics to identify GIT1 S46 as PKD3 substrate, siRNA knockdown of PKD3, phosphomimetic (S46D) and phospho-deficient (S46A) GIT1 mutants, immunofluorescence imaging of GIT1 localization and paxillin The Journal of biological chemistry High 22893698
2019 PKD3 is the predominant PKD isoform in hepatocytes and provides negative feedback on insulin signaling by suppressing AKT, mTORC1, and mTORC2 activity. Hepatic deletion of PKD3 in mice improves insulin-induced glucose tolerance but increases SREBP-mediated lipogenesis and hepatic triglyceride/cholesterol content on a high-fat diet. Constitutively active PKD3 overexpression causes insulin resistance. Hepatic-specific PKD3 knockout mouse, constitutively active PKD3 overexpression mouse model, glucose tolerance tests, Western blotting for AKT/mTORC1/mTORC2, SREBP pathway analysis, lipid measurements Science signaling High 31387939
2019 PKD3 interacts with SREBP1 in prostate cancer cells, promotes maturation of SREBP1 (68 kDa form), and enhances SREBP1 binding to the FASN promoter to upregulate de novo lipogenesis. PKD3 silencing reduces lipid content and expression of FASN and ACLY; overexpression of SREBP1 rescues the growth suppression caused by PKD3 depletion. Co-immunoprecipitation (PKD3–SREBP1), ChIP (SREBP1 at FASN promoter), siRNA knockdown, SREBP1 overexpression rescue, lipid content assays, Western blotting Journal of Cancer Medium 31772672
2008 PKD3 is the predominant PKD isoform in mouse exocrine pancreatic acinar cells. It undergoes rapid membrane translocation, trans-activating phosphorylation, and kinase activation after gastrointestinal hormone or cholinergic stimulation via a Ca2+-independent, diacylglycerol- and PKC-dependent mechanism. PKD3 activation potentiates MEK/ERK/RSK signaling and enhances cholecystokinin-mediated amylase secretion. Differential PKD isoform expression analysis, membrane fractionation/translocation assays, pharmacological PKC inhibition, ERK/RSK Western blotting, amylase secretion assay in isolated acinar cells The Journal of biological chemistry Medium 19028687
2005 The C1a domain of PKD3 is responsible for high-affinity phorbol ester ([3H]PDBu) binding, while C1b has no detectable binding activity. Both C1a and PKD3 kinase activity are required for phorbol ester (PMA)-induced plasma membrane translocation of PKD3. PKC, by directly activating PKD3, regulates its plasma membrane localization. Radioligand binding assay ([3H]PDBu), C1a/C1b point mutations, GFP-tagged PKD3 live-cell imaging, constitutively active and kinase-dead PKD3 constructs, PKC inhibitor RO 31-8220 Cellular signalling High 15927450
2010 PKD3 co-localizes with the androgen receptor (AR) in the nucleus of LNCaP cells after DHT stimulation. Wild-type PKD3 significantly increases AR transcriptional activity and PSA expression in response to DHT; kinase-dead PKD3 partially reduces AR transcriptional activity, indicating kinase activity is required. Dual-luciferase AR reporter assay, RT-QPCR for PSA mRNA, confocal microscopy for PKD3/AR co-localization, overexpression of wild-type vs. kinase-dead PKD3 Nan fang yi ke da xue xue bao (Journal of Southern Medical University) Medium 20813663
2016 PKD3 deficiency in mouse embryonic fibroblasts impairs microtubule nucleation and dynamics during the cell cycle. PKD1 can partially compensate for PKD3 function in this process. Genetic PKD3 knockout MEFs, microtubule nucleation and dynamics assays, cell cycle analysis Cell cycle (Georgetown, Tex.) Medium 27245420
2016 PKD2 and PKD3 are activated in cardiomyocytes and cardiac fibroblasts by sphingosine-1-phosphate, thrombin, PDGF, and H2O2 via PKC-dependent pathways. A novel role for Rho was identified in sphingosine-1-phosphate and thrombin receptor-dependent activation of PKD2/3 and downstream CREB phosphorylation in cardiomyocytes. Phos-tag SDS-PAGE, PKC inhibitor GF109203X, Rho inhibitor C3 toxin, CREB phosphorylation assays, in isolated cardiac fibroblasts and cardiomyocytes Journal of molecular and cellular cardiology Medium 27515283
2010 PKD1 and PKD3 are both activated by orexin-A (via orexin receptor 1) and translocate to the plasma membrane. Overexpression of kinase-dead PKD1 or kinase-dead PKD3 disrupts orexin-A-induced calcium oscillations, demonstrating a functional role for PKD3 kinase activity in modulating Ca2+ responses. Phosphospecific antibody detection of PKD1/PKD3 activation, dominant-negative (kinase-dead) PKD1 and PKD3 overexpression, intracellular calcium imaging in HEKOx1R cells Biochimica et biophysica acta Medium 20621130
2019 The RhoGEF GEF-H1 acts upstream of PKD3 activation in triple-negative breast cancer stem cells. PKD3 is required for maintenance of the TNBC stem cell population, as its depletion reduces cancer stem cell frequency in vitro and tumor initiation potential in vivo. PKD3 siRNA knockdown, in vitro oncosphere and colony formation assays, in vivo tumor initiation assay, pharmacological PKD inhibition combined with paclitaxel International journal of cancer Medium 31745977
2021 PKD3 activates PKA and regulates PKA-mediated glucose and tyrosine metabolism in hepatocytes. PKD3 is activated by glucagon and promotes glucose and tyrosine levels in hepatocytes. Identified >300 putative PKD3 substrates by phosphoproteomics, including phenylalanine hydroxylase (PAH) as a downstream PKA target. Phosphoproteomics on PKD3-deficient hepatocytes, biochemical PKA activity assays, glucagon stimulation, glucose and tyrosine metabolite measurements Life science alliance Medium 34145024
2023 Hsp90 physically interacts with PKD3 to ensure its conformational stability. Pharmacological Hsp90 inhibition causes proteasomal degradation of PKD3 and abrogates PKD3-dependent prostate cancer cell migration. PKD3 is thus an Hsp90 client protein. Proximity ligation assay, co-immunoprecipitation (Hsp90–PKD3), Hsp90 inhibitor (ganetespib) treatment, proteasome inhibition rescue, PKD3 siRNA combined with ganetespib, ectopic PKD3 overexpression in LNCaP cells Cells Medium 36672148
2026 PRKCN (PKD3) physically interacts with mTOR and activates mTORC1/C2 signaling to sustain IRF4 expression in multiple myeloma. PRKCN and IRF4 form a feed-forward transcriptional circuit: IRF4 directly induces PRKCN transcription, and PRKCN fosters IRF4 expression via mTOR. This function is independent of PKD3 kinase activity but requires activation-loop phosphorylation. Co-immunoprecipitation (PRKCN–mTOR), constitutive/inducible knockdown, kinase-dead mutant analysis, ChIP-seq/luciferase for IRF4-PRKCN circuit, in vivo xenograft models, pharmacological PRKCN inhibitor Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 41655233
2025 Endogenous PKD3 localizes to Rab7-positive late endosomes in MDA-MB-231 TNBC cells cultured on stiff matrices. PKD3 depletion results in smaller Rab7-positive vesicles, reduced retromer complex recruitment, enhanced cathepsin D secretion, impaired endosomal acidification, dysregulated Wnt signaling, and a decline in cancer stemness. Endogenous PKD3 localization by immunofluorescence, siRNA PKD3 knockdown, Rab7 vesicle size quantification, retromer recruitment assay, cathepsin D secretion assay, endosomal pH measurement, Wnt signaling and stemness assays iScience Medium 40970203

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Protein kinase D3 (PKD3) contributes to prostate cancer cell growth and survival through a PKCepsilon/PKD3 pathway downstream of Akt and ERK 1/2. Cancer research 111 18483269
2012 PKD2 and PKD3 promote prostate cancer cell invasion by modulating NF-κB- and HDAC1-mediated expression and activation of uPA. Journal of cell science 85 22797919
2021 TRIM47 activates NF-κB signaling via PKC-ε/PKD3 stabilization and contributes to endocrine therapy resistance in breast cancer. Proceedings of the National Academy of Sciences of the United States of America 60 34433666
2016 Snail-activated long non-coding RNA PCA3 up-regulates PRKD3 expression by miR-1261 sponging, thereby promotes invasion and migration of prostate cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 48 27743381
2013 Elevated protein kinase D3 (PKD3) expression supports proliferation of triple-negative breast cancer cells and contributes to mTORC1-S6K1 pathway activation. The Journal of biological chemistry 48 24337579
2019 The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling. Science signaling 30 31387939
2019 Interplay of PKD3 with SREBP1 Promotes Cell Growth via Upregulating Lipogenesis in Prostate Cancer Cells. Journal of Cancer 30 31772672
2013 Evidence of a third ADPKD locus is not supported by re-analysis of designated PKD3 families. Kidney international 29 23760289
2008 PKD3 is the predominant protein kinase D isoform in mouse exocrine pancreas and promotes hormone-induced amylase secretion. The Journal of biological chemistry 28 19028687
2021 PKD3 promotes metastasis and growth of oral squamous cell carcinoma through positive feedback regulation with PD-L1 and activation of ERK-STAT1/3-EMT signalling. International journal of oral science 26 33692335
2012 GIT1 phosphorylation on serine 46 by PKD3 regulates paxillin trafficking and cellular protrusive activity. The Journal of biological chemistry 23 22893698
2016 Lack of PRKD2 and PRKD3 kinase domain somatic mutations in PRKD1 wild-type classic polymorphous low-grade adenocarcinomas of the salivary gland. Histopathology 21 26426580
2019 The GEF-H1/PKD3 signaling pathway promotes the maintenance of triple-negative breast cancer stem cells. International journal of cancer 19 31745977
2016 Phos-tag SDS-PAGE resolves agonist- and isoform-specific activation patterns for PKD2 and PKD3 in cardiomyocytes and cardiac fibroblasts. Journal of molecular and cellular cardiology 18 27515283
2016 PKD3 deficiency causes alterations in microtubule dynamics during the cell cycle. Cell cycle (Georgetown, Tex.) 14 27245420
2021 A phosphoproteomic approach reveals that PKD3 controls PKA-mediated glucose and tyrosine metabolism. Life science alliance 13 34145024
2020 PRKD3 promotes malignant progression of OSCC by downregulating KLF16 expression. European review for medical and pharmacological sciences 11 33378018
2005 Individual C1 domains of PKD3 in phorbol ester-induced plasma membrane translocation of PKD3 in intact cells. Cellular signalling 11 15927450
2010 A role for PKD1 and PKD3 activation in modulation of calcium oscillations induced by orexin receptor 1 stimulation. Biochimica et biophysica acta 9 20621130
2023 Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration. Cells 6 36672148
2022 Addressing the role of PKD3 in the T cell compartment with knockout mice. Cell communication and signaling : CCS 4 35440091
2025 Transcriptome Analysis Suggests PKD3 Regulates Proliferative Glucose Metabolism, Calcium Homeostasis and Microtubule Dynamics After MEF Spontaneous Immortalization. International journal of molecular sciences 1 39859313
2025 Effect of PRKD3 on cell cycle in gastric cancer progression and downstream regulatory networks. Medical oncology (Northwood, London, England) 1 40131654
2025 Primary Sweat Gland Adenocarcinoma of the Skin With ATL2::PRKD3 Fusion: A Potential Cutaneous Analog of Cribriform Adenocarcinoma of the Salivary Glands? Genes, chromosomes & cancer 1 41225782
2024 PRKD3 promotes proliferation of liver cancer cells: a downstream proteomics profiling study. American journal of translational research 1 39678603
2026 Targeting PRKCN, an Essential Driver Orchestrating mTOR-IRF4 Axis Independently of Kinase Activity, in Multiple Myeloma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41655233
2026 [Effect of Trifolium repens extract on OSC-4 cell proliferation, apoptosis and NLRP3/PRKD3 protein level]. Shanghai kou qiang yi xue = Shanghai journal of stomatology 0 41928531
2026 PRKD3 Overexpression May Improve Survival and Suppresses Proliferation in Colorectal Cancer. Cancer reports (Hoboken, N.J.) 0 41980898
2025 PKD3 localizes to late endosomes to maintain Rab7-dependent endolysosomal homeostasis. iScience 0 40970203
2024 T cell-intrinsic PKD3 fine-tunes differentiation into CD8+ central memory T cells and CD8 single positive thymocyte development. Immunology 0 38798068
2010 [PKD3 contributes to up-regulation of prostate-specific antigen in prostate cancer cells]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 0 20813663

Missed literature

Know a paper Affinage missed for PRKD3? Flag it for the maintainers and the community.

No submissions yet.