MYCBP

MYCBP (AMY-1) is a small adaptor protein that couples transcriptional control to multiple signaling outputs, functioning both as a co-activator of MYC and as a competitive regulator of PKA scaffolding (PMID:9797456, PMID:12414807). It binds via its C-terminal region to the N-terminal transactivation domain of c-MYC and stimulates E-box-dependent transcription by the MYC/Max complex without contacting DNA directly (PMID:9797456), with nuclear entry tied to elevated c-myc and S-phase progression (PMID:9797456). In parallel, MYCBP engages the RII-binding regions of AKAP scaffolds—AKAP149/S-AKAP84, AKAP95, and AKAP84—forming ternary complexes with the PKA regulatory subunit II that exclude the catalytic subunit and suppress PKA activity, anchoring the protein to mitochondria, cytoplasm, and nucleus depending on the partner (PMID:11483602, PMID:12414807); in testis it extends to a quaternary mitochondrial complex with AAT-1α (PMID:12223483). MYCBP also localizes to the trans-Golgi network through interaction with the ARF-GEF BIG2 (PMID:16866877). In Hedgehog signaling, MYCBP resides in a nuclear complex with Gli and Sufu, and upon pathway activation and Sufu dissociation it promotes Gli-mediated target gene expression downstream of Patched, Smoothened, and the primary cilium (PMID:25403183). MYCBP abundance is set by the ubiquitin–proteasome system: the E3 ligase CBLB drives K48-linked ubiquitination at K20 to target it for degradation (PMID:42191055), while circ_0002669 binding shields it to sustain c-Myc target expression (PMID:38570856). In Drosophila, MYCBP assembles with Sakura and Otu and is essential for germline stem cell self-renewal and differentiation via Dpp/BMP signaling and sex-lethal splicing (PMID:41325460).

1. 1998 High

   Established MYCBP's founding molecular function—how a small protein could amplify MYC transcriptional output without DNA contact—by mapping it as a transactivation-domain binding co-activator.

   Evidence Two-hybrid screen, reciprocal deletion-mapped Co-IP, and E-box reporter assays

   PMID:9797456

   Open questions at the time

   • Structural basis of the C-terminal MYCBP/MYC TAD interface unresolved
   • Whether co-activation requires additional bridging factors not defined
2. 1998 Medium

   Addressed where MYCBP acts by linking its nuclear import to c-myc levels and S-phase, suggesting regulated subcellular partitioning.

   Evidence Immunofluorescence with cell-cycle synchronization and transient transfection

   PMID:9797456

   Open questions at the time

   • Import machinery and signal driving translocation not identified
   • Single-lab correlation rather than direct trafficking assay
3. 2000 Medium

   Tested MYCBP's cellular consequence beyond transcription, showing gain-of-function drives erythroid differentiation, hinting at a MYC-independent role.

   Evidence Stable overexpression in K562 with ε-globin RT-PCR and AraC differentiation assay

   PMID:10639579

   Open questions at the time

   • Molecular pathway linking MYCBP to ε-globin induction undefined
   • Whether effect is MYC-dependent not resolved
4. 2001 High

   Opened a second functional axis by showing MYCBP binds AKAP scaffolds and RII to form a mitochondrial PKA-anchoring complex, placing it in cAMP signaling.

   Evidence Two-hybrid, in vitro binding, Co-IP, and subcellular fractionation in HeLa and sperm

   PMID:11483602

   Open questions at the time

   • Functional consequence of mitochondrial anchoring not yet measured here
   • Relationship to MYC role unclear
5. 2002 High

   Defined the mechanistic output of the AKAP association—competitive binding that blocks the PKA catalytic subunit and suppresses kinase activity—establishing MYCBP as a PKA modulator.

   Evidence In vitro binding with AKAP95/AKAP84 and direct PKA activity assays

   PMID:12414807

   Open questions at the time

   • Physiological settings where this suppression dominates not mapped
   • Quantitative competition with native RII in cells not measured
6. 2002 Medium

   Extended the PKA complex in testis to a quaternary assembly with AAT-1α, a PKA substrate, linking MYCBP scaffolding to spermatogenic signaling.

   Evidence Two-hybrid, reciprocal Co-IP, co-localization, and in vitro phosphorylation assay

   PMID:12223483

   Open questions at the time

   • In vivo functional role in spermatogenesis not tested
   • Single-lab evidence
7. 2002 Low

   Identified an additional testis-specific partner (AMAP-1), reinforcing a spermatogenesis-associated interactome.

   Evidence Two-hybrid, Co-IP, and immunofluorescence co-localization

   PMID:12151104

   Open questions at the time

   • Single Co-IP/colocalization with no functional mechanism defined
   • Spermatogenesis role inferred, not demonstrated
8. 2003 Medium

   Resolved how MYCBP itself is transcriptionally controlled, identifying Sp1-dependent basal expression and GATA-1 synergy in erythroid cells.

   Evidence Reporter deletion assays and EMSA of the AMY-1 promoter in HeLa/K562

   PMID:12620400

   Open questions at the time

   • Signals upstream of GATA-1/Sp1 control not defined
   • Single-lab promoter analysis
9. 2006 Medium

   Added a Golgi localization mode, showing TGN targeting depends specifically on the ARF-GEF BIG2 rather than BIG1.

   Evidence FLAG-MYCBP Co-IP, immunofluorescence, and RNAi epistasis of BIG1/BIG2

   PMID:16866877

   Open questions at the time

   • Functional role of MYCBP at the TGN unknown
   • How TGN pool relates to nuclear/PKA roles unclear
10. 2014 High

    Placed MYCBP in Hedgehog signaling as a nuclear Gli/Sufu complex component that promotes Gli activity upon pathway activation, defining a transcriptional role beyond MYC.

    Evidence Proteomic screen, Co-IP, ChIP on Hh targets, reporter assays, and zebrafish epistasis

    PMID:25403183

    Open questions at the time

    • Mechanism by which MYCBP enhances Gli at promoters not detailed
    • Connection between Hh role and MYC co-activation unexplored
11. 2019 Medium

    Connected MYCBP transcription to Wnt/β-catenin signaling, showing EYA4 dephosphorylation of β-catenin Ser552 limits β-catenin/LEF1-driven MYCBP expression.

    Evidence EYA4 overexpression/KO with siRNA rescue, qRT-PCR, and promoter analysis in HCC cells

    PMID:31385398

    Open questions at the time

    • Direct β-catenin/LEF1 occupancy of MYCBP promoter inferred, not directly shown
    • Single-lab cancer-cell context
12. 2024 Medium

    Revealed post-translational stabilization of MYCBP, showing circ_0002669 binds and protects it from proteasomal degradation to sustain c-Myc target genes.

    Evidence Biotin pulldown/MS, RNA-IP, luciferase, and functional rescue

    PMID:38570856

    Open questions at the time

    • Ubiquitin machinery counteracted by circ_0002669 not identified in this study
    • Single-lab evidence
13. 2026 Medium

    Identified the degradative arm of MYCBP turnover, mapping CBLB-mediated K48 ubiquitination at K20 that limits c-Myc pathway activity.

    Evidence Co-IP, ubiquitination assay, K20 site mutagenesis, and knockdown/overexpression functional assays

    PMID:42191055

    Open questions at the time

    • Signals controlling CBLB engagement of MYCBP unknown
    • Single-lab evidence
14. 2025 High

    Established an in vivo developmental requirement, showing Drosophila MYCBP partners with Sakura and Otu to sustain germline stem cell self-renewal via Dpp/BMP signaling and sex-lethal splicing.

    Evidence Co-IP of binary/ternary complexes, null mutant phenotyping, germline RNAi, and BMP/sxl readouts

    PMID:41325460

    Open questions at the time

    • Whether mammalian MYCBP has an analogous stem-cell role untested
    • Direct molecular function of MYCBP within the Sakura/Otu complex undefined

• How MYCBP's distinct activities—MYC co-activation, PKA suppression, Gli regulation, and Golgi targeting—are coordinated or mutually exclusive within a cell remains unresolved.
• No structure of MYCBP or its complexes
• No unified model integrating its transcriptional and scaffolding roles
• Mammalian loss-of-function phenotype not defined in the corpus