Affinage

PDE4DIP

Myomegalin · UniProt Q5VU43

Round 2 corrected
Length
2346 aa
Mass
265.1 kDa
Annotated
2026-04-29
40 papers in source corpus 9 papers cited in narrative 9 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PDE4DIP (myomegalin) is a large coiled-coil scaffolding protein that organizes cAMP signaling microdomains by anchoring PDE4D and PKA to the Golgi apparatus and centrosome, thereby controlling compartmentalized cyclic nucleotide signaling, cytoskeletal organization, and cell fate decisions. It directly binds PDE4D3 and cooperates with AKAP9 to stabilize PKA regulatory subunit RIIα at the Golgi; loss of this scaffolding mislocalizes PKA RIIα, derepresses PKA/CREB signaling, and triggers apoptosis and cell-cycle arrest (PMID:11134006, PMID:39905234). PDE4DIP also recruits PLCγ/PKCε to the Golgi, promoting PKCε-mediated degradation of the RAS-GAP neurofibromin (NF1) and thereby sustaining oncogenic RAS/ERK signaling in KRAS-mutant colorectal cancer (PMID:37355626). A deleterious PDE4DIP missense variant (p.A123T) impairs PDE4D compartmentalization, elevates cAMP, and alters β2-adrenergic and desmin phosphorylation, contributing epistatically with a DES mutation to early-onset atrial fibrillation and conduction disease (PMID:34289528).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2000 High

    Establishing PDE4DIP as a PDE4D-anchoring scaffold resolved how PDE4D is tethered to particulate structures at the Golgi/centrosome, providing the first mechanistic basis for subcellular cAMP compartmentalization.

    Evidence Co-immunoprecipitation of PDE4D3 with myomegalin, immunocytochemistry showing co-localization at Golgi/centrosome in COS-7 cells and skeletal muscle

    PMID:11134006

    Open questions at the time
    • Which PDE4D splice variants besides PDE4D3 are anchored by myomegalin
    • No structural resolution of the PDE4D–myomegalin binding interface
    • Functional consequence of disrupting the interaction in vivo not tested
  2. 2006 Medium

    Identification of PDE4DIP as a DISC1 interactor expanded its network beyond cAMP scaffolding into cytoskeletal and cell-division pathways, though the functional significance for PDE4DIP itself was not defined.

    Evidence Iterative yeast two-hybrid screen with mammalian cell verification

    PMID:17043677

    Open questions at the time
    • Binding interface and stoichiometry of DISC1–PDE4DIP interaction undefined
    • No reciprocal Co-IP or endogenous validation reported
    • Whether this interaction modulates cAMP signaling or centrosome function unknown
  3. 2011 Medium

    Orthogonal proteomics confirmed PDE4DIP as a bona fide centrosomal component in human cells, corroborating the original dual Golgi/centrosome localization.

    Evidence PCP-SILAC mass spectrometry and BAC transgene live-cell imaging of human centrosomes

    PMID:21399614

    Open questions at the time
    • Which isoform(s) localize to centrosomes versus Golgi not resolved
    • Functional role at the centrosome (e.g., microtubule nucleation, ciliogenesis) not addressed
  4. 2021 Medium

    A disease-linked PDE4DIP missense mutation (p.A123T) established that impaired PDE4D/PKA compartmentalization elevates cAMP, dysregulates β2-adrenergic receptor and desmin phosphorylation, and contributes to cardiac arrhythmia, providing the first human-genetic validation of the scaffolding model.

    Evidence Whole-exome sequencing with familial segregation, cAMP assays, PKA phosphorylation readouts, co-localization imaging of mutant PDE4DIP with PDE4D

    PMID:34289528

    Open questions at the time
    • Epistatic interaction with DES mutation complicates attribution of phenotype to PDE4DIP alone
    • No knock-in animal model to confirm pathogenicity in vivo
    • Structural basis for how A123T disrupts PDE4D binding unknown
  5. 2023 Medium

    Discovery that PDE4DIP recruits PLCγ/PKCε to the Golgi to degrade NF1 and sustain RAS/ERK signaling revealed a second, cAMP-independent scaffolding function with direct oncogenic consequences.

    Evidence Co-IP of PDE4DIP–PLCγ–PKCε complex, shRNA knockdown restoring NF1 expression and inhibiting ERK, in vivo xenograft validation in KRAS-mutant colorectal cancer

    PMID:37355626

    Open questions at the time
    • Whether the PLCγ/PKCε scaffolding function is independent of or integrated with PDE4D anchoring
    • Mechanism by which PKCε drives NF1 degradation (proteasomal/lysosomal) not fully resolved
    • Generalizability beyond KRAS-mutant colorectal cancer unclear
  6. 2025 Medium

    Identification of the PDE4DIP–AKAP9 complex as the mechanism that stabilizes PKA RIIα at the Golgi showed that PDE4DIP integrates two anchoring systems — one for PDE4 and one for PKA — to coordinate opposing arms of cAMP signaling at the same compartment.

    Evidence Reciprocal Co-IP of PDE4DIP–AKAP9, shRNA knockdown showing RIIα mislocalization and degradation, PKA/CREB activation, apoptosis and cell-cycle arrest in NSCLC cells, xenograft validation

    PMID:39905234

    Open questions at the time
    • Whether PDE4DIP binds AKAP9 directly or through an intermediary not fully resolved
    • Relative contribution of PDE4DIP versus AKAP9 to RIIα Golgi retention not dissected
    • Findings limited to NSCLC cell lines; relevance to normal physiology not demonstrated
  7. 2025 Medium

    Reciprocal overexpression/knockdown experiments in cardiomyocytes demonstrated that PDE4DIP negatively regulates Rho-ROCK signaling, cytoskeletal organization, and mitochondrial energy metabolism, linking it to left ventricular non-compaction pathophysiology.

    Evidence Overexpression and knockdown in H9C2 and primary rat cardiomyocytes with electron microscopy, ATP assays, western blotting for Rho-ROCK markers

    PMID:40612665

    Open questions at the time
    • Direct molecular target through which PDE4DIP inhibits Rho-ROCK not identified
    • Whether Rho-ROCK regulation depends on PDE4D/PKA scaffolding or is an independent function
    • No in vivo cardiac-specific model validating non-compaction phenotype
  8. 2025 Medium

    Validation of PDE4DIP mRNA as a direct miR-21-5p target established a post-transcriptional regulatory axis (SORBS2/miR-21-5p/PDE4DIP) through which PDE4DIP expression is suppressed in PM2.5-exposed NSCLC, positioning PDE4DIP as a tumor suppressor in that context.

    Evidence Luciferase reporter assay confirming miR-21-5p targeting of PDE4DIP 3′UTR, shRNA knockdown promoting xenograft growth

    PMID:41378000

    Open questions at the time
    • Tumor-suppressive mechanism downstream of PDE4DIP loss not delineated
    • Whether the miR-21-5p axis operates in non-lung cancer contexts unknown
    • Apparent contradiction with KRAS-mutant CRC data where PDE4DIP is oncogenic not reconciled

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of PDE4DIP's multi-partner scaffolding, whether its PDE4D-anchoring and PLCγ/PKCε-recruiting functions operate independently or are coordinated, and how tissue context determines whether PDE4DIP acts as a tumor promoter or suppressor.
  • No crystal or cryo-EM structure of any PDE4DIP complex
  • Relative physiological importance of individual scaffolding functions not dissected in vivo
  • Context-dependent oncogenic versus tumor-suppressive roles remain contradictory across cancer types

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4
Localization
GO:0005794 Golgi apparatus 3 GO:0005815 microtubule organizing center 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 3
Partners
AKAP9DISC1NF1PDE4DPLCG1PRKAR2APRKCE

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Myomegalin (PDE4DIP) was identified as a novel Golgi/centrosome protein that directly binds PDE4D, anchoring it to particulate structures. Myomegalin is a large 2,324-amino acid protein with coiled-coil domains and a leucine zipper homologous to Drosophila centrosomin. Expressed in COS-7 cells, it co-immunoprecipitated with PDE4D3 and sequestered it to particulate fractions, and immunocytochemistry showed co-localization of PDE4D and myomegalin at the Golgi/centrosomal area of cultured cells and in sarcomeric structures of skeletal muscle. Co-immunoprecipitation, immunocytochemistry, transfection/overexpression in COS-7 cells, subcellular fractionation The Journal of biological chemistry High 11134006
2011 PDE4DIP was identified as a novel centrosomal component by complementary proteomics methods (PCP-SILAC mass spectrometry and BAC transgeneOmics), confirming its localization to human centrosomes. PCP-SILAC mass spectrometry, BAC transgene live-cell imaging, antibody localization screen The EMBO journal Medium 21399614
2006 PDE4DIP was identified as an interacting partner of DISC1 (Disrupted in Schizophrenia 1) via iterative yeast two-hybrid screens, placing PDE4DIP in a network associated with cytoskeletal stability, intracellular transport, and cell-cycle/division. Yeast two-hybrid screening, mammalian cell verification of interactions Molecular psychiatry Medium 17043677
2021 A deleterious missense mutation in PDE4DIP (p.A123T) was found to impair compartmentalization of PKA and PDE4D: the mutant showed reduced co-localization with PDE4D, increased cAMP levels leading to higher PKA phosphorylation of the β2-adrenergic receptor, and decreased PKA phosphorylation of desmin after isoproterenol stimulation. This epistatic interaction with a DES (desmin) mutation drives early-onset atrial fibrillation and conduction disease. In vitro functional characterization of mutant PDE4DIP, co-localization imaging, cAMP assays, PKA phosphorylation assays (immunofluorescence, biochemical), whole exome sequencing with familial segregation Human mutation Medium 34289528
2022 PDE4DIP functions as an anchoring protein that generates dynamic cAMP microdomains by tethering PDE4 and PKA to specific subcellular compartments. Genetic mutations in PDE4DIP lead to altered intracellular targeting, blunted responsiveness to adrenergic stimulation, pathological cardiac remodeling, and arrhythmias. Review synthesizing genetic and functional data (supports mechanistic model from experimental studies) Cellular signalling Low 35346821
2023 PDE4DIP promotes constitutive activation of PKCε by recruiting PLCγ/PKCε to the Golgi apparatus, leading to PKCε-mediated degradation of the RAS GTPase-activating protein NF1 (neurofibromin). This suppression of NF1 enables full activation of oncogenic RAS/ERK signaling in KRAS-mutant colorectal cancer cells. Knockdown of PDE4DIP restored NF1 expression, inhibited RAS/ERK signaling, and impaired cancer cell growth and MEK inhibitor resistance. shRNA knockdown, overexpression, co-immunoprecipitation (PLCγ/PKCε/PDE4DIP complex), western blotting for NF1/RAS/ERK pathway components, tumor xenograft in vivo, MEK inhibitor resistance assays Cell death & disease Medium 37355626
2025 PDE4DIP coordinates with A-kinase anchoring protein 9 (AKAP9) to enhance Golgi localization and stability of PKA regulatory subunit RIIα. Depletion of PDE4DIP mislocalizes PKA RIIα away from the Golgi and leads to its degradation, thereby releasing negative regulation of PKA signaling and triggering apoptosis and cell cycle arrest via PKA/CREB pathway activation in NSCLC cells. shRNA knockdown, overexpression, co-immunoprecipitation (PDE4DIP-AKAP9 complex), immunofluorescence localization of PKA RIIα, western blotting, in vitro proliferation assays, in vivo xenograft Communications biology Medium 39905234
2025 PDE4DIP overexpression in cardiomyocytes induced cytoskeletal disorganization, decreased ATP content and cell migration, increased cell proliferation, and mitochondrial vacuolation, while inhibiting Rho-ROCK signaling-related gene and protein expression. Conversely, PDE4DIP knockdown promoted cytoskeleton formation, elevated ATP content, and enhanced cell migration. These findings place PDE4DIP as a regulator of cell polarity, cytoskeletal organization, and energy metabolism through the Rho-ROCK pathway in the context of left ventricular non-compaction. Overexpression and knockdown in H9C2 cells and primary rat cardiomyocytes, electron microscopy, MitoTracker staining, ATP assay, western blotting, immunofluorescence, scratch/wound healing assay, CCK-8 proliferation assay Genes & diseases Medium 40612665
2025 miR-21-5p directly targets PDE4DIP mRNA (validated by luciferase reporter assay), suppressing PDE4DIP expression in NSCLC cells exposed to PM2.5. Knockdown of PDE4DIP promoted NSCLC tumor growth in vivo, while SORBS2 suppressed tumorigenesis by inhibiting miR-21-5p and thereby restoring PDE4DIP expression, placing PDE4DIP downstream of a SORBS2/miR-21-5p axis as a tumor suppressor in this context. Luciferase reporter assay (miR-21-5p targeting PDE4DIP 3'UTR), shRNA knockdown, miRNA mimic/inhibitor, in vivo xenograft, MTT/colony formation/transwell assays Translational cancer research Medium 41378000

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 3411 32353859
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 Generation and analysis of 280,000 human expressed sequence tags. Genome research 376 8889549
2006 Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Molecular psychiatry 345 17043677
2011 Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods. The EMBO journal 265 21399614
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2004 Functional proteomics mapping of a human signaling pathway. Genome research 247 15231748
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2013 Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS. Nature methods 170 23455922
2000 Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase. The Journal of biological chemistry 162 11134006
2009 Ubiquitin-mediated proteolysis of HuR by heat shock. The EMBO journal 142 19322201
2022 A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets. Nature biotechnology 140 36217030
2000 Shotgun sequencing of the human transcriptome with ORF expressed sequence tags. Proceedings of the National Academy of Sciences of the United States of America 135 10737800
2018 Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma. Nature communications 57 30030436
2006 The dermal microenvironment induces the expression of the alternative activation marker CD301/mMGL in mononuclear phagocytes, independent of IL-4/IL-13 signaling. Journal of leukocyte biology 49 16849611
2021 Epistatic interaction of PDE4DIP and DES mutations in familial atrial fibrillation with slow conduction. Human mutation 17 34289528
2022 PDE4DIP in health and diseases. Cellular signalling 15 35346821
2014 Mouse macrophage galactose-type lectin (mMGL) is critical for host resistance against Trypanosoma cruzi infection. International journal of biological sciences 11 25170304
2023 PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis. Cell death & disease 6 37355626
2025 Dysfunction of PDE4DIP contributes to LVNC development by regulating cell polarity, skeleton, and energy metabolism via Rho-ROCK pathway. Genes & diseases 2 40612665
2025 The PDE4DIP-AKAP9 axis promotes lung cancer growth through modulation of PKA signalling. Communications biology 1 39905234
2025 Circular RNA Pde4dip regulates myogenesis by interacting with Zfp143 mRNA: a novel regulatory axis. RNA biology 1 41170695
2025 PM2.5 promotes non-small cell lung cancer tumorigenesis by miR-21-5p targeting PDE4DIP accumulated. Translational cancer research 0 41378000