Affinage

PRKD2

Serine/threonine-protein kinase D2 · UniProt Q9BZL6

Length
878 aa
Mass
96.7 kDa
Annotated
2026-06-10
14 papers in source corpus 9 papers cited in narrative 9 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

PRKD2 is a serine/threonine protein kinase whose catalytic activity, dependent on the activation-loop threonine (T714 in human; T757 in zebrafish), is indispensable for cardiac outflow tract development (PMID:33597201). As a signaling kinase, PRKD2 phosphorylates the transcriptional repressor Bcl6 to sequester it in the cytoplasm, thereby constraining T follicular helper cell differentiation; Bcl6 in turn represses PRKD2 expression, establishing a mutually inhibitory feedback loop in CD4+ T cells (PMID:31980486). In cancer cells, PRKD2 is held stable by HSP90 and is required for hypoxia-induced HIF1α accumulation and NF-κB activation that drive VEGF-A secretion and tumor angiogenesis (PMID:25297628), and it cooperates with AMAP1 and GTP-loaded Rab5c downstream of EGFR to recycle β1 integrins and promote breast cancer invasion (PMID:22734003). PRKD2 also operates downstream of the GABP transcription factor in hematopoietic stem cell cycle entry and CML pathogenesis (PMID:23345428), and acts as a brake on pancreatic β-cell insulin secretion by limiting L-type Ca2+ channel expression and glucose-stimulated Ca2+ influx, such that its loss causes hyperinsulinemia preceding insulin resistance (PMID:29789568). PRKD2 expression is itself controlled post-transcriptionally by METTL3-mediated m6A modification of its mRNA (PMID:36058761).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2012 Medium

    Defined how PRKD2 is integrated into receptor-driven membrane trafficking, answering how it contributes to cancer cell invasion at the molecular level.

    Evidence Direct binding and Co-IP with AMAP1/β1 integrin plus Rab5c manipulation in breast cancer invasion assays

    PMID:22734003

    Open questions at the time
    • Whether PRKD2 kinase activity (vs. scaffolding) is required for integrin recycling not resolved
    • No identified PRKD2 substrate within the trafficking complex
  2. 2013 Medium

    Placed PRKD2 in a transcriptional hierarchy by identifying GABP as a direct upstream regulator governing its expression in hematopoietic stem cells.

    Evidence Gabpα genetic knockout, target identification, and PRKD2 ectopic rescue of BCR-ABL cell growth

    PMID:23345428

    Open questions at the time
    • Downstream PRKD2 effectors in HSC cycle entry not defined
    • Direct binding of GABP to the PRKD2 locus inferred bioinformatically
  3. 2014 Medium

    Established the determinants of PRKD2 protein stability and its role in the hypoxic angiogenic response, explaining why HSP90 inhibition impairs tumor angiogenesis.

    Evidence Reciprocal Co-IP, proteasome-rescue of HSP90-inhibited degradation, and HIF1α/NF-κB/VEGF-A readouts with in vivo tumor models

    PMID:25297628

    Open questions at the time
    • Direct kinase substrate linking PRKD2 to HIF1α/NF-κB not identified
    • Single lab
  4. 2018 High

    Revealed an unanticipated metabolic role, showing PRKD2 restrains β-cell insulin secretion by limiting L-type Ca2+ channel activity.

    Evidence PRKD2 knockout mouse with β-cell electrophysiology/Ca2+ imaging and insulin secretion assays, corroborated by a natural primate nonsense mutation

    PMID:29789568

    Open questions at the time
    • Whether PRKD2 phosphorylates the channel directly not established
    • Tissue-specific contributions to systemic phenotype unresolved
  5. 2020 High

    Defined a direct kinase-substrate relationship and feedback circuit, explaining how PRKD2 controls T follicular helper cell fate.

    Evidence Forward genetic screen and null mouse, Co-IP and phosphorylation assay, Bcl6 nuclear/cytoplasmic fractionation, and TFH/germinal center flow cytometry

    PMID:31980486

    Open questions at the time
    • Phosphorylation site(s) on Bcl6 not mapped
    • Mechanism of Bcl6-mediated repression of PRKD2 not detailed
  6. 2021 Medium

    Demonstrated that PRKD2 catalytic activity, not merely its presence, is required for an organ developmental program (cardiac outflow tract).

    Evidence Zebrafish forward genetic screen, activation-loop point mutation (T757A) with kinase activity assays and cardiovascular phenotyping

    PMID:33597201

    Open questions at the time
    • Relevant developmental substrates downstream of PRKD2 not identified
    • TBX5 link to PRKD2 only suggested as a potential regulator
  7. 2022 Medium

    Identified post-transcriptional control of PRKD2 via m6A and linked PRKD2 to glucose handling in skeletal muscle.

    Evidence m6A and mRNA stability assays with METTL3 perturbation, PRKD2 silencing, and GLUT4/p-AKT readouts in C2C12 cells and HFD mice

    PMID:36058761

    Open questions at the time
    • Direct kinase mechanism connecting PRKD2 to GLUT4/AKT not established
    • Specific m6A sites on PRKD2 mRNA not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct catalytic substrates that mediate PRKD2's diverse roles (angiogenesis, integrin recycling, Ca2+ channel regulation, developmental signaling) remain largely unidentified.
  • Few direct PRKD2 phosphorylation substrates beyond Bcl6 are mapped
  • Mechanistic links to Notch1 and TP53/CDKN1A rest only on Low-confidence knockdown correlations

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 1
Partners
AMAP1BCL6GABPHSP90ITGB1RAB5C

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 AMAP1 directly binds PRKD2 and forms a complex with the cytoplasmic tail of β1 integrin subunit; GTP-Rab5c also binds AMAP1, and EGFR signaling activates Rab5c to promote intracellular association of AMAP1 and PRKD2, enabling β1 integrin recycling and breast cancer cell invasion. Direct binding assay, Co-immunoprecipitation, functional invasion assays with dominant-negative/activated Rab5c The Journal of cell biology Medium 22734003
2014 HSP90 binds to and stabilizes PRKD2 protein in human cancer cells; pharmacologic HSP90 inhibition triggers proteasome-dependent degradation of PRKD2. PRKD2 is essential for hypoxia-induced accumulation of HIF1α and activation of NF-κB, and ectopic PRKD2 expression restores HIF1α and secreted VEGF-A levels in hypoxic cancer cells treated with HSP90 inhibitors. Co-immunoprecipitation (HSP90-PRKD2 binding), pharmacologic inhibition with proteasome inhibitor rescue, ectopic expression and knockdown with HIF1α/NF-κB/VEGF-A readouts, in vivo tumor angiogenesis models Cancer research Medium 25297628
2013 GABP transcription factor directly controls PRKD2 expression in hematopoietic stem cells; deletion of Gabpα markedly reduces Prkd2 expression, and PRKD2 rescue restores growth of Gabpα-null BCR-ABL-expressing cells, placing PRKD2 downstream of GABP in the HSC cell cycle entry and CML development pathway. Genetic knockout (Gabpα deletion), bioinformatic target identification, expression analysis (qRT-PCR/Western blot), pharmacologic inhibition of PRKD2, ectopic PRKD2 expression rescue Proceedings of the National Academy of Sciences of the United States of America Medium 23345428
2018 PRKD2 deficiency in mice promotes pancreatic β-cell insulin hypersecretion by increasing expression and activity of L-type Ca2+ channels, thereby augmenting high glucose- and membrane depolarization-induced Ca2+ influx; this leads to hyperinsulinemia which precedes insulin resistance. PRKD2 knockout mouse model, electrophysiology/Ca2+ imaging in β-cells, Western blot for L-type Ca2+ channel expression, glucose tolerance and insulin secretion assays Nature communications High 29789568
2020 PRKD2 directly binds Bcl6 and phosphorylates Bcl6 to constrain it to the cytoplasm, thereby limiting T follicular helper (TFH) cell development; conversely, Bcl6 represses PRKD2 expression in CD4+ T cells to commit them to TFH development, forming a mutually inhibitory feedback loop. Forward genetic screen (missense mutation in Prkd2), targeted Prkd2 null mouse model, Co-immunoprecipitation (PRKD2-Bcl6 binding), phosphorylation assay, nuclear/cytoplasmic fractionation of Bcl6, flow cytometry for TFH and germinal center B cells Science immunology High 31980486
2021 A T757A substitution (equivalent to T714A in human PRKD2) in the kinase domain activation loop of zebrafish Prkd2 disrupts catalytic activity and causes outflow tract stenosis and cardiovascular defects, demonstrating that PRKD2 kinase activity is indispensable for cardiac outflow tract development; TBX5 was identified as a potential regulator of PRKD2. Zebrafish forward genetic screen, identification of point mutation in prkd2, kinase activity assays, in vivo cardiovascular phenotyping, pharmacologic treatment (Cyclosporin A sensitivity), marker expression analysis Biology open Medium 33597201
2022 METTL3-mediated m6A modification of PRKD2 mRNA reduces its stability; downregulation of METTL3 increases PRKD2 expression by reducing m6A levels and promoting PRKD2 mRNA stability, and PRKD2 promotes glucose uptake and reduces oxidative stress through GLUT4 and p-AKT signaling in skeletal muscle cells. m6A methylation assay, METTL3 overexpression/knockdown, PRKD2 silencing, mRNA stability assay, Western blot for GLUT4/p-AKT/METTL3/PRKD2, glucose uptake assay in C2C12 cells and HFD mouse model Nutrition, metabolism, and cardiovascular diseases Medium 36058761
2019 PRKD2 regulates the Notch1 pathway in AML cells; PRKD2 knockdown induces apoptosis and increases chemosensitivity, while PRKD2 overexpression promotes proliferation and chemoresistance, with Notch1 pathway activity following PRKD2 expression levels. siRNA knockdown and lentiviral overexpression of PRKD2, CCK-8 proliferation assay, flow cytometry apoptosis, Western blot for Notch1 pathway components OncoTargets and therapy Low 31849496
2023 PRKD2 knockdown in cervical cancer cells increases chemotherapy sensitivity via the TP53/CDKN1A pathway, leading to G1 cell cycle arrest and apoptosis. siRNA knockdown of PRKD2, CCK-8 viability, flow cytometry apoptosis, Western blot for TP53/CDKN1A, immunohistochemistry on patient tissues Current cancer drug targets Low 36017858

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Rab5c promotes AMAP1-PRKD2 complex formation to enhance β1 integrin recycling in EGF-induced cancer invasion. The Journal of cell biology 90 22734003
2014 HSP90 supports tumor growth and angiogenesis through PRKD2 protein stabilization. Cancer research 52 25297628
2022 Quercetin ameliorated insulin resistance via regulating METTL3-mediated N6-methyladenosine modification of PRKD2 mRNA in skeletal muscle and C2C12 myocyte cell line. Nutrition, metabolism, and cardiovascular diseases : NMCD 26 36058761
2018 Deficiency of PRKD2 triggers hyperinsulinemia and metabolic disorders. Nature communications 25 29789568
2013 GABP transcription factor is required for development of chronic myelogenous leukemia via its control of PRKD2. Proceedings of the National Academy of Sciences of the United States of America 25 23345428
2014 Loss-of-function RNAi screens in breast cancer cells identify AURKB, PLK1, PIK3R1, MAPK12, PRKD2, and PTK6 as sensitizing targets of rapamycin activity. Cancer letters 22 25193464
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
2020 Mutual inhibition between Prkd2 and Bcl6 controls T follicular helper cell differentiation. Science immunology 19 31980486
2019 PRKD2 Promotes Progression and Chemoresistance of AML via Regulating Notch1 Pathway. OncoTargets and therapy 9 31849496
2015 PRKD2: A two-pronged kinase crucial for the tumor-supporting activity of HSP90. Molecular & cellular oncology 9 27308444
2023 Knockdown of PRKD2 Enhances Chemotherapy Sensitivity in Cervical Cancer via the TP53/CDKN1A Pathway. Current cancer drug targets 4 36017858
2021 A zebrafish forward genetic screen identifies an indispensable threonine residue in the kinase domain of PRKD2. Biology open 2 33597201
2025 Single-cell and bulk transcriptomics uncovers PRKD2-driven tumor stemness and progression in multiple myeloma. Scientific reports 1 41120632
2025 PRKD2 as a novel target for targeting the diabetes-osteoporosis nexus. Scientific reports 0 39922871

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