FAM117B

FAM117B is an adaptor-type regulator of KEAP1/NRF2 signaling that promotes oncogenic and stress-response programs. It competes with NRF2 for binding to KEAP1, reducing ubiquitination-mediated degradation of NRF2 and thereby activating the KEAP1/NRF2 pathway to drive gastric cancer cell growth and chemoresistance in an NRF2-dependent manner (PMID:36719368). FAM117B also physically interacts with DYRK1A and acts upstream of it; activated DYRK1A phosphorylates PLK2 and raises PLK2 levels to promote colorectal cancer proliferation, migration, invasion, and metastasis (PMID:41504297). Within a GLCCI1-controlled DYRK1A/FAM117B axis, this activity converges on KEAP1/NRF2 to restrain mitochondrial dysfunction in bronchial epithelial cells (PMID:40490147). The biochemical basis of the FAM117B–DYRK1A regulatory step has not been reconstituted in the available corpus.

1. 2023 High

   Established the first molecular mechanism for FAM117B, showing it stabilizes NRF2 by competing for KEAP1 rather than acting through an unrelated route.

   Evidence Co-IP, ubiquitination and competitive binding assays with NRF2-dependent rescue in gastric cancer cell and tumor models

   PMID:36719368

   Open questions at the time

   • No structural definition of the FAM117B–KEAP1 interface
   • Whether NRF2 stabilization is the sole oncogenic output of FAM117B not established
2. 2025 Medium

   Placed FAM117B in a GLCCI1-regulated DYRK1A axis upstream of KEAP1/NRF2 controlling mitochondrial homeostasis, extending its role beyond cancer to epithelial stress responses.

   Evidence GLCCI1 overexpression with NRF2 ubiquitination and mitochondrial function assays in OVA-stimulated bronchial epithelial cells and an allergic asthma mouse model

   PMID:40490147

   Open questions at the time

   • FAM117B's specific molecular step within the DYRK1A axis not dissected
   • Direct GLCCI1–FAM117B relationship not demonstrated
3. 2026 Medium

   Defined a direct FAM117B–DYRK1A interaction and a downstream DYRK1A–PLK2 effector arm, identifying a second signaling branch through which FAM117B drives metastasis.

   Evidence Reciprocal Co-IP, Western blotting, and genetic epistasis rescue (DYRK1A OE vs FAM117B KD; PLK2 KD vs DYRK1A OE) in colorectal cancer cells with subcutaneous and splenic-to-liver metastasis models

   PMID:41504297

   Open questions at the time

   • No in vitro kinase reconstitution confirming direct phosphorylation driven by the FAM117B–DYRK1A complex
   • Mechanism by which FAM117B activates DYRK1A unknown
   • Single-lab finding without independent replication

• How FAM117B integrates its KEAP1/NRF2-stabilizing function with its DYRK1A-activating function remains unresolved.
• No structural model of FAM117B
• Biochemical mechanism of DYRK1A activation undefined
• Whether the two branches operate in the same cells or pathways unknown