PDLIM7

PDLIM7 (Enigma) is a multidomain cytoskeletal scaffold and E3 ubiquitin ligase that couples actin-based architecture and integrin adhesions to transcriptional and signaling outputs (PMID:20042479, PMID:30404826). Through its PDZ domain it binds α-actinin to localize at F-actin stress fibers and integrin adhesions, while its LIM domains and PY motif engage signaling and effector proteins, allowing it to organize the actin cytoskeleton and maintain contractile cell phenotypes (PMID:20042479, PMID:27470516, PMID:30404826). In mechanotransduction, force recruits PDLIM7 from the cytoplasm to adhesions where it binds YAP via the YAP C-terminal PDZ-binding motif to drive YAP/TAZ nuclear localization and TEAD-dependent transcription (PMID:30404826); this interface is competitively antagonized by TPM2, which displaces YAP and promotes its cytoplasmic sequestration and inactivation (PMID:36823643). PDLIM7 also controls developmental transcription factor activity, regulating nuclear/cytoplasmic shuttling of Tbx5 at the cardiac atrio-ventricular boundary (PMID:19895804). As an E3 ligase, PDLIM7 stabilizes MDM2 by inhibiting its self-ubiquitination, thereby enhancing MDM2-directed p53 ubiquitination and degradation in a serum/SRF-induced pathway, and modulates MDM2 turnover during CDK4/6-inhibitor-induced senescence (PMID:21060154, PMID:29789718). It additionally polyubiquitinates the NF-κB p65 subunit and heterodimerizes with PDLIM2, using p62/SQSTM1 to bridge ubiquitinated PDLIM2 to the proteasome and suppress proinflammatory cytokine production (PMID:32849529). PDLIM7 is itself a substrate of the E3 ligase Nedd4-1, ubiquitinated through a PY-motif–WW-domain interaction, linking its turnover to denervation-associated skeletal muscle atrophy (PMID:26556890).

1. 1998 High

   Established PDLIM7 as a localization scaffold linking a receptor tyrosine kinase to subcellular positioning required for mitogenic signaling.

   Evidence Co-IP, dominant-negative and chimeric coexpression, and subcellular localization studies of Ret/ptc2

   PMID:9528800

   Open questions at the time

   • Did not define the structural basis of LIM-domain binding to the tyrosine 586 site
   • Relevance beyond Ret/ptc2 signaling not addressed
2. 2005 Medium

   Connected PDLIM7 to insulin-responsive actin remodeling by identifying LIM-domain binding to the APS NPTY motif.

   Evidence Yeast two-hybrid, co-IP in HEK293, immunofluorescence colocalization, and NPTY-motif mutagenesis

   PMID:15946664

   Open questions at the time

   • No in vitro reconstitution of the APS/Enigma complex
   • Functional consequence for insulin signaling outputs not quantified
3. 2009 High

   Demonstrated in vivo that PDLIM7 controls a transcription factor's nucleocytoplasmic shuttling, governing Tbx5 activity during heart development.

   Evidence Zebrafish morpholino knockdown with epistasis and target-gene expression analysis (nppa, tbx2b)

   PMID:19895804

   Open questions at the time

   • Direct PDLIM7–Tbx5 binding interface not mapped
   • Mechanism of shuttling control not biochemically defined
4. 2009 Medium

   Consolidated the domain logic of the ALP/Enigma family, assigning α-actinin binding to the PDZ domain and signaling-protein binding to LIM domains in muscle scaffolding.

   Evidence Review synthesizing prior binding and functional studies

   PMID:20042479

   Open questions at the time

   • Review-level synthesis, not new primary data
   • PDLIM7-specific contributions not separated from paralogs
5. 2010 High

   Defined PDLIM7 as a positive regulator of MDM2 that suppresses p53, revealing an SRF-driven mitogenic survival pathway.

   Evidence In vitro ubiquitination assays, co-IP, apoptosis assays, mouse xenografts, and SRF binding assays

   PMID:21060154

   Open questions at the time

   • Whether PDLIM7 directly ubiquitinates any substrate here versus modulating MDM2 not fully resolved
   • Structural basis of MDM2–p53 ternary complex formation undefined
6. 2015 High

   Identified PDLIM7 as a Nedd4-1 substrate, placing its own turnover under E3-ligase control relevant to muscle atrophy.

   Evidence Co-IP, ubiquitination assay, PY-motif domain mapping, and Nedd4-1 muscle-specific knockout mice

   PMID:26556890

   Open questions at the time

   • Functional consequence of PDLIM7 loss for atrophy not directly demonstrated by PDLIM7 manipulation
   • Ubiquitin chain topology on PDLIM7 not characterized
7. 2016 Medium

   Showed PDLIM7 maintains the contractile smooth muscle phenotype through cytoskeletal organization, restraining proliferation.

   Evidence siRNA knockdown in cultured SMCs with cytoskeleton imaging, spreading and proliferation assays, and H3K27ac ChIP-seq

   PMID:27470516

   Open questions at the time

   • Single lab, cultured cells only
   • Direct molecular link between cytoskeletal disruption and marker downregulation not established
8. 2018 High

   Established PDLIM7 as a force-recruited adaptor driving YAP/TAZ nuclear localization and TEAD transcription via α-actinin and the YAP PDZ-binding motif.

   Evidence siRNA knockdown, co-IP, live-cell imaging, force application, and reporter assays

   PMID:30404826

   Open questions at the time

   • How PDLIM7 promotes YAP nuclear import mechanistically not resolved
   • Redundancy with PDLIM5 not fully dissected
9. 2018 Medium

   Extended PDLIM7's MDM2 regulation to a senescence context, implicating it in CDK4/6-inhibitor-induced MDM2 downregulation.

   Evidence CDK4/6 inhibitor treatment, Western blotting, and knockdown in human cell lines

   PMID:29789718

   Open questions at the time

   • Direction of MDM2 regulation here differs in context from stabilization model; reconciliation not provided
   • Single lab
10. 2020 High

    Demonstrated PDLIM7 acts as a direct E3 ligase against NF-κB p65 and partners with PDLIM2/p62 to suppress inflammatory signaling.

    Evidence In vitro ubiquitination, co-IP, siRNA double knockdown, cytokine measurement, and proteasome inhibition

    PMID:32849529

    Open questions at the time

    • Catalytic domain of PDLIM7 responsible for ligase activity not mapped
    • In vivo physiological role in inflammation not tested
11. 2023 Medium

    Revealed competitive regulation of the PDLIM7–YAP1 axis by TPM2 in prostate cancer, controlling YAP1 nuclear transport and stability.

    Evidence Co-IP, competition and PDZ-binding motif mutagenesis, immunofluorescence, and in vivo tumor assays

    PMID:36823643

    Open questions at the time

    • Single lab
    • Generality beyond prostate cancer cells not established

• How PDLIM7's scaffolding and intrinsic E3-ligase activities are mechanistically coordinated, and which catalytic determinants drive its ubiquitination of substrates, remain unresolved.
• No structural model of the catalytic/substrate-binding interface
• Context-dependent opposing effects on MDM2 not reconciled
• In vivo physiological roles of the ligase functions largely untested