PLEK2

PLEK2 is an oncogenic scaffolding/adaptor protein that drives cancer cell migration, invasion, and epithelial-mesenchymal transition across multiple solid tumor types (PMID:31498891, PMID:31182136). It operates largely by controlling the stability and activity of signaling proteins through ubiquitination-dependent mechanisms: it binds the kinase domain of EGFR and shields it from c-CBL-mediated ubiquitination to sustain EGFR signaling (PMID:31182136), and it interacts with SHIP2 to target it for ubiquitin-dependent degradation, thereby relieving inhibition of PI3K/AKT signaling and promoting EMT and invasion (PMID:31498891). PLEK2 also binds c-Myc and displaces FBXW7, preventing proteasomal degradation of c-Myc, while c-Myc reciprocally activates PLEK2 transcription to form a positive feedback loop (PMID:36002342). Convergence on PI3K/AKT signaling is a recurring theme downstream of PLEK2 (PMID:31498891, PMID:35122599). PLEK2 additionally interacts with cofilin-1 (CFL1) to remodel the cytoskeleton during nicotine-induced cancer progression (PMID:37921560). PLEK2 transcription is induced by upstream regulators including TGF-β/Smad2/3 (PMID:34601488), BRD4 (PMID:35122599), and α5-nAChR/STAT3 signaling (PMID:37921560), and PLEK2 lies downstream of PIK3CD in glioma (PMID:35851857). Downstream effectors mediating its motility phenotypes include CCL2 (PMID:31182136) and LCN2 (PMID:34601488).

1. 2019 Medium

   Established a first biochemical mechanism for PLEK2 oncogenicity by showing it physically protects a receptor tyrosine kinase from degradation, explaining sustained pro-migratory signaling.

   Evidence Mass spectrometry, reciprocal Co-IP, and ubiquitination assays in gallbladder cancer cells, with RNA-seq and a mouse metastasis model identifying CCL2 as a downstream effector

   PMID:31182136

   Open questions at the time

   • Does not define the structural basis of the PLEK2-EGFR kinase domain interaction
   • Does not establish whether PLEK2 competes with c-CBL directly or acts allosterically
   • CCL2 induction linked correlatively to EGFR signaling, not by direct biochemical step
2. 2019 Medium

   Showed PLEK2 can also act as a destabilizer rather than a stabilizer, targeting the lipid phosphatase SHIP2 for degradation to activate PI3K/AKT and drive EMT.

   Evidence Co-IP, ubiquitination assays, and overexpression/knockdown functional assays in NSCLC cells

   PMID:31498891

   Open questions at the time

   • Does not identify the E3 ligase PLEK2 recruits to SHIP2
   • Does not reconcile how PLEK2 protects EGFR yet degrades SHIP2 mechanistically
3. 2021 Medium

   Identified the upstream transcriptional driver of PLEK2, placing it within the TGF-β signaling axis, and defined a downstream effector for its motility phenotype.

   Evidence Luciferase reporter and ChIP assays for Smad2/3 promoter binding, plus RNA-seq and rescue experiments identifying LCN2 in oesophageal squamous cell carcinoma

   PMID:34601488

   Open questions at the time

   • Does not link Smad2/3 induction of PLEK2 to a specific protein-level mechanism
   • Mechanism connecting PLEK2 to LCN2 expression not defined
4. 2021 Low

   Reinforced PLEK2 as an upstream activator of PI3K/AKT/mTOR signaling in a distinct tumor context.

   Evidence Knockdown with western blot pathway readout and xenograft in osteosarcoma cells

   PMID:34084215

   Open questions at the time

   • Single western-blot pathway readout for pathway placement
   • No direct biochemical mechanism linking PLEK2 to PI3K/AKT in this context
5. 2022 High

   Provided the most rigorous mechanism: PLEK2 stabilizes the oncogenic transcription factor c-Myc by blocking FBXW7 access, and c-Myc reciprocally transcribes PLEK2, establishing a self-amplifying feed-forward loop.

   Evidence Co-IP, cycloheximide chase, ubiquitination assays, ChIP-qPCR, and luciferase reporter assays in head and neck squamous cell carcinoma

   PMID:36002342

   Open questions at the time

   • Does not map the PLEK2 region required for c-Myc binding or FBXW7 displacement
   • Does not quantify the contribution of the feedback loop to tumor maintenance in vivo
6. 2022 Medium

   Added a second transcriptional activator, BRD4, linking epigenetic readers to PLEK2 expression and its downstream PI3K/AKT axis.

   Evidence ChIP, siRNA and JQ-1 pharmacological inhibition with functional assays in NSCLC

   PMID:35122599

   Open questions at the time

   • Does not establish whether BRD4 acts directly or via intermediary transcription factors
   • PI3K/AKT placement downstream of PLEK2 inferred from pathway readout
7. 2022 Medium

   Placed PLEK2 genetically downstream of PIK3CD (p110δ), connecting it to a defined PI3K isoform-driven migration program in glioma.

   Evidence CRISPR/Cas9 knockout of PIK3CD with profiler PCR array, RNA-seq, and functional/in vivo assays in GBM cells

   PMID:35851857

   Open questions at the time

   • Does not establish whether PIK3CD regulates PLEK2 transcriptionally or post-transcriptionally
   • Direct biochemical link absent
8. 2023 Medium

   Connected PLEK2 to cytoskeletal remodeling through a direct interaction with cofilin-1, and embedded it in a nicotine/α5-nAChR/STAT3 induction pathway.

   Evidence Co-IP, xenograft, human tissue immunostaining, and functional assays in lung adenocarcinoma

   PMID:37921560

   Open questions at the time

   • Does not define how PLEK2-CFL1 binding alters cofilin activity
   • Single Co-IP without reciprocal mapping of interaction interface
9. 2023 Low

   Extended PLEK2 function to immune evasion by linking it to PD-L1 expression and T-cell suppression in gastric cancer.

   Evidence siRNA knockdown, western blot, flow cytometry, and T-cell co-culture with hyperthermia treatment

   PMID:38147897

   Open questions at the time

   • No direct biochemical mechanism linking PLEK2 to PD-L1 regulation
   • Correlation between PLEK2 and PD-L1 not mechanistically resolved
10. 2024 Low

    Reported additional candidate partners and effectors broadening the PLEK2 interaction and signaling repertoire.

    Evidence Co-IP with SPC25 in lung adenocarcinoma (PMID 38894536) and RNA-seq/western blot linking PLEK2 to MMP1 via IL-17/ERK/STAT3 in PDAC (PMID 39117976)

    PMID:38894536 PMID:39117976

    Open questions at the time

    • Single Co-IP for the PLEK2-SPC25 interaction without reciprocal validation
    • No direct biochemical mechanism for the PLEK2-MMP1 link

• How a single adaptor reconciles opposing activities (stabilizing EGFR and c-Myc while degrading SHIP2) and what its structural determinants of partner selection are remain unresolved.
• No structural model of PLEK2 or its interaction interfaces
• E3 ligase machinery PLEK2 recruits to SHIP2 unidentified
• Whether PLEK2's pleckstrin-homology lipid binding contributes to membrane signaling untested in this corpus