VGLL1

VGLL1 is a transcriptional co-activator that partners with TEAD transcription factors to control programs of cell proliferation, invasion, and lineage specification (PMID:22632831, PMID:38233381). It engages TEAD via a conserved Tondu (VxxHF) motif and binds the same TEAD surface used by the Hippo effectors YAP and TAZ, despite lacking the Ω-loop element required for high-affinity binding by VGLL2 and Drosophila Vestigial; this Tondu-only mode of binding is functionally equivalent to Vestigial, as human VGLL1 substitutes for Vg in Drosophila wing formation (PMID:10518497, PMID:22632831, PMID:33060790). VGLL1-TEAD complexes activate targets including IGFBP-5, MMP9, EGFR, HMGA1, and HPV early genes, and this output is gated by TGF-β/ERK/RSK2-driven phosphorylation of VGLL1 at serine 84, which is required for TEAD4 binding and downstream invasion and proliferation (PMID:22632831, PMID:33069758, PMID:32132238, PMID:39356622, PMID:38439973). In human trophectoderm specification, VGLL1 acts downstream of GATA2/3 and TFAP2A/C yet is essential for full trophoblast identity, remodeling chromatin accessibility through histone acetylation with TEAD4, GATA3, and TFAP2C, reinforcing GATA3 and WNT signaling, and directly inducing the H3K27me3 demethylase KDM6B to activate bivalent trophoblast promoters (PMID:38233381, PMID:41284866). Across placental, pancreatic, and cancer cells VGLL1 binds chromatin at TEAD, AP-1, and GATA motifs to drive shared invasion and proliferation programs, and it is recurrently upregulated in cancer through epigenetic and epitranscriptomic mechanisms—H3K27ac reprogramming under endocrine therapy and METTL3/IGF2BP2-mediated m6A modification—making the VGLL1-TEAD interface a pharmacological target in therapy-resistant tumors (PMID:39356622, PMID:38439973, PMID:38912065).

1. 1999 High

   Established that human VGLL1 (TONDU) is a functional TEAD partner by showing it carries a Vestigial-homologous domain that interacts with all mammalian TEAD factors and can replace Vestigial in vivo.

   Evidence Protein interaction assays plus Drosophila UAS-GAL4 ectopic rescue of wing formation

   PMID:10518497

   Open questions at the time

   • Did not define the structural basis of the interaction
   • No mammalian transcriptional target identified
2. 2012 High

   Resolved how VGLL1 docks onto TEAD and linked the interaction to a proliferative output, showing it occupies the same TEAD4 surface as YAP/TAZ and drives IGFBP-5 expression and anchorage-independent growth.

   Evidence X-ray crystallography of the Vgll1-TEAD4 complex with luciferase reporter and soft-agar assays

   PMID:22632831

   Open questions at the time

   • Did not address regulation of VGLL1 activity
   • Cancer relevance in vivo not tested
3. 2014 Medium

   Defined the minimal VGLL1 TEAD-binding motif, showing nanomolar binding via a β-strand:loop:α-helix element despite lacking a secondary structure required by YAP/TAZ.

   Evidence Biophysical peptide-TEAD4 binding assays with mutagenesis-guided analysis

   PMID:24504694

   Open questions at the time

   • In vitro peptide binding only
   • Functional consequence of mouse-human difference not established
4. 2020 High

   Identified the signaling input that switches VGLL1 on, showing TGF-β/ERK/RSK2 phosphorylates VGLL1 at S84 to enable TEAD4 binding and MMP9-driven invasion in gastric cancer.

   Evidence Site-directed mutagenesis, co-IP, kinase assay, reporter and invasion/proliferation assays

   PMID:33069758

   Open questions at the time

   • Whether S84 phosphorylation regulates other targets unknown
   • Phosphatase counter-regulation not defined
5. 2020 Medium

   Clarified the evolutionary and structural logic of VGLL-TEAD binding, showing VGLL1 and VGLL3 bind TEAD via the Tondu motif alone whereas VGLL2 and Vg require an additional Ω-loop.

   Evidence Structural and binding assays comparing VGLL family members with Ω-loop mutagenesis

   PMID:33060790

   Open questions at the time

   • Functional consequence of Tondu-only binding for target selection unresolved
6. 2020 High

   Extended VGLL1 function to viral oncogenesis, showing VGLL1/TEAD1 occupies the HPV16 LCR to drive early gene expression and cervical cancer cell growth.

   Evidence siRNA knockdown, DNA pulldown, ChIP, reporter and proliferation assays in cervical keratinocytes/cancer cells

   PMID:32132238

   Open questions at the time

   • Whether VGLL1 acts on host as well as viral promoters in this context not detailed
7. 2024 High

   Defined VGLL1 as an essential chromatin remodeler in human trophectoderm, cooperating with TEAD4, GATA3, and TFAP2C to control accessibility and self-renewal.

   Evidence CRISPR KO, ChIP-seq for histone acetylation, ATAC-seq, co-IP, and differentiation assays in TELCs/TSCs

   PMID:38233381

   Open questions at the time

   • Direct target genes downstream of chromatin remodeling not fully enumerated
8. 2024 Medium

   Revealed a TEAD-independent VGLL1 function, showing cytoplasmic TAZ stabilization that promotes EGFR and tumor-initiating cell frequency while repressing AXL and CD24.

   Evidence Co-IP, knockdown/overexpression, domain-deletion constructs, flow cytometry, Western blot

   PMID:38417636

   Open questions at the time

   • Single lab, single study
   • Mechanism of TAZ nuclear expulsion not resolved
9. 2024 High

   Connected VGLL1 to endocrine therapy resistance, showing ER-degrader-induced H3K27ac reprogramming upregulates VGLL1 to drive TEAD-dependent EGFR transcription, with the VGLL1-TEAD4 interface as a druggable node.

   Evidence H3K27ac ChIP-seq, RNA-seq, pharmacological VGLL1-TEAD4 disruption, proliferation and EGFR inhibitor assays

   PMID:39356622

   Open questions at the time

   • In vivo efficacy of interface disruption not established here
10. 2024 Medium

    Defined an epitranscriptomic route to VGLL1 overexpression and its metastatic effector, showing METTL3/IGF2BP2 m6A modification raises VGLL1, which with TEAD4 activates HMGA1 to drive Wnt/EMT metastasis.

    Evidence MeRIP/m6A-seq, co-IP, HMGA1 rescue, mouse models, invasion/proliferation assays

    PMID:38439973

    Open questions at the time

    • Single lab study
    • Whether HMGA1 is a direct VGLL1/TEAD target promoter not fully resolved
11. 2024 Medium

    Mapped the genome-wide VGLL1 chromatin binding landscape, showing TEAD, AP-1, and GATA6 motif occupancy and ~3,000 shared targets across placental and cancer cell types driving invasion/proliferation.

    Evidence ChIP-seq, RNA-seq, invasion and proliferation assays

    PMID:38912065

    Open questions at the time

    • Direct vs indirect target distinction limited
    • Single study
12. 2025 High

    Positioned VGLL1 hierarchically in trophectoderm, showing it acts downstream of GATA2/3 and TFAP2A/C yet is required for full trophoblast identity via EGFR/GATA3 feedback, WNT regulation, and direct induction of KDM6B-mediated H3K27me3 removal.

    Evidence PSC BMP4 TE induction, ATAC-seq, RNA-seq, ChIP-seq, loss-of-function, epistasis

    PMID:41284866

    Open questions at the time

    • Mechanism of KDM6B recruitment by VGLL1 not detailed

• How VGLL1 selects between TEAD-dependent transcriptional activation and TEAD-independent TAZ stabilization, and what determines its context-specific target gene repertoire, remains unresolved.
• No unified model integrating phosphorylation, partner availability, and chromatin context
• TEAD-independent mechanism rests on a single study