FAM117B

FAM117B is a KEAP1-binding protein that competitively displaces NRF2 from the KEAP1–NRF2 complex, thereby inhibiting NRF2 ubiquitination and activating NRF2-dependent transcriptional programs that promote cell survival and chemoresistance (PMID:36719368). FAM117B also physically interacts with and activates DYRK1A kinase, establishing a FAM117B→DYRK1A→PLK2 signaling axis that drives cancer cell proliferation and metastasis (PMID:41504297). In airway epithelial cells, FAM117B operates downstream of GLCCI1 and DYRK1A to activate NRF2 signaling and protect mitochondrial function during allergic inflammation (PMID:40490147).

1. 2013 Medium

   Proteomic mapping of the KEAP1 interactome established that ETGE-motif-containing proteins competitively displace NRF2 from KEAP1, providing the mechanistic framework within which FAM117B was later classified as a KEAP1 competitor.

   Evidence Affinity purification mass spectrometry of the KEAP1 interactome with competitive binding assays

   PMID:23382044

   Open questions at the time

   • FAM117B was not individually validated in this study; its membership in the KEAP1-competitor class was inferred from later work
   • The stoichiometry and affinity of FAM117B–KEAP1 binding relative to NRF2 remain uncharacterized
2. 2023 High

   Direct biochemical and functional validation demonstrated that FAM117B binds KEAP1, competitively displaces NRF2, blocks NRF2 ubiquitination, and that FAM117B-driven gastric cancer growth and chemoresistance are NRF2-dependent, establishing the core mechanism linking FAM117B to NRF2 pathway activation.

   Evidence Reciprocal Co-IP, ubiquitination assays, NRF2 knockdown rescue, in vitro and in vivo tumor growth models in gastric cancer

   PMID:36719368

   Open questions at the time

   • Structural basis of the FAM117B–KEAP1 interaction (e.g., whether FAM117B uses a canonical ETGE motif) is unresolved
   • Whether FAM117B expression is itself regulated by NRF2 (potential feedback loop) has not been tested
3. 2023 Low

   High-throughput interactome mapping placed FAM117B within the DYRK1A protein interaction network, opening the question of whether FAM117B regulates or is regulated by DYRK1A kinase.

   Evidence AP-MS interactome survey across multiple human cell lines

   PMID:37900285

   Open questions at the time

   • No functional validation of the FAM117B–DYRK1A interaction was performed; awaits reciprocal Co-IP and functional assays
   • Whether FAM117B is a substrate or regulator of DYRK1A was not addressed
4. 2025 Medium

   Placing FAM117B downstream of GLCCI1/DYRK1A and upstream of NRF2, this study showed the DYRK1A/FAM117B axis protects mitochondrial function in allergic airway inflammation by inhibiting NRF2 ubiquitination, bridging the DYRK1A interaction to the KEAP1/NRF2 mechanism.

   Evidence OVA-induced allergic asthma mouse model, bronchial epithelial cells with GLCCI1 overexpression, mitochondrial readouts (membrane potential, ROS, ATP, mtDNA), NRF2 ubiquitination assays

   PMID:40490147

   Open questions at the time

   • How DYRK1A biochemically activates FAM117B (e.g., direct phosphorylation, stabilization) is not defined
   • Single-lab finding; independent replication in additional asthma models needed
5. 2026 Medium

   Epistatic rescue experiments established a linear FAM117B→DYRK1A→PLK2 signaling axis in which FAM117B activates DYRK1A-mediated phosphorylation and stabilization of PLK2, driving colorectal cancer proliferation and metastasis.

   Evidence Co-IP, phosphorylation assays, knockdown/overexpression epistasis, in vivo colorectal cancer and liver metastasis models

   PMID:41504297

   Open questions at the time

   • The molecular mechanism by which FAM117B activates DYRK1A (allosteric activation, scaffolding, or other) is unknown
   • Whether the DYRK1A–PLK2 axis and the KEAP1–NRF2 axis represent parallel or convergent outputs of FAM117B has not been tested
   • Single-lab finding; independent confirmation in additional cancer types needed

• The biochemical mechanism by which FAM117B activates DYRK1A, whether FAM117B is itself a DYRK1A phosphosubstrate, the structural basis of FAM117B–KEAP1 binding, and the integration of the DYRK1A and NRF2 branches of FAM117B signaling remain open questions.
• No structural data for FAM117B or its complexes exist
• Whether FAM117B functions in non-cancer, non-asthma physiological contexts is unexplored
• Regulation of FAM117B expression and protein stability is uncharacterized