FAM135B

FAM135B is a cancer-associated, multifunctional scaffold protein that promotes tumor cell survival, proliferation, and DNA damage repair, first identified through whole-genome/exome sequencing as a gene capable of driving malignancy in esophageal squamous cell carcinoma (ESCC) (PMID:24670651). It acts largely through direct protein-protein interactions that reconfigure signaling and repair complexes: it binds the growth factor GRN (progranulin) to engage a feedforward AKT/mTOR loop that sustains proliferation, with loss of FAM135B increasing radiosensitivity and synergizing with mTOR inhibition (PMID:33323378, PMID:33340561). In the DNA damage response, FAM135B binds the chromodomain of the TIP60 (KAT5) acetyltransferase, enhances its activity, and maintains pre-assembled TIP60-ATM complexes under resting conditions; upon damage it is released, and it promotes both homologous recombination and non-homologous end-joining, accelerating clearance of γH2AX and 53BP1 foci (PMID:35979619). FAM135B further controls genome-maintenance gene expression by synergizing with SRPK1 to drive nuclear SRSF1 translocation, directing alternative splicing of FAAP20 to activate the Fanconi Anemia pathway and confer chemoresistance (PMID:39397154). Additional interactions tie FAM135B to migration and immune/inflammatory signaling: it binds TNIK to activate Wnt/β-catenin signaling and EMT (PMID:38881420), stabilizes IFI16 by competitively blocking TRIM21-mediated ubiquitination to initiate STING signaling (PMID:41218197), and binds the IKK complex to suppress NF-κB/IL-6-driven angiogenesis (PMID:42260484). Its expression is positively controlled upstream by METTL3-mediated m6A modification (PMID:38881420) and HNF4A-driven transcription (PMID:42260484). A distinct role in neuronal biology is indicated by the requirement of FAM135B for survival and neurite integrity of spinal motor neurons (PMID:30391288).

1. 2014 Medium

   Established FAM135B as a previously uncharacterized gene with oncogenic capacity, motivating mechanistic dissection of how it promotes malignancy.

   Evidence Whole-genome/whole-exome sequencing followed by functional malignancy assays in ESCC cell lines

   PMID:24670651

   Open questions at the time

   • No molecular mechanism or interaction partner identified
   • Driver versus passenger role not resolved
2. 2018 Medium

   Revealed a non-cancer role by showing FAM135B is required for motor neuron survival and neurite integrity, broadening its functional scope beyond tumor biology.

   Evidence siRNA knockdown in iPSC-derived spinal motor neurons with survival and neurite morphology readouts; microarray profiling of SBMA neurons

   PMID:30391288

   Open questions at the time

   • Molecular pathway underlying neuronal survival role unknown
   • No mechanistic link to the cancer functions established
3. 2018 Low

   Provided the first hint of a functional relationship between FAM135B and KAT5/TIP60, via an inverse expression correlation in patient tissue.

   Evidence Immunohistochemistry on paired ESCC and adjacent tissues with correlation analysis

   PMID:29502064

   Open questions at the time

   • Observational correlation only, no functional validation of regulation
   • Direction and mechanism of the FAM135B-KAT5 relationship unresolved
4. 2020 Medium

   Defined the first direct molecular partner and signaling axis, showing FAM135B binds GRN to drive an AKT/mTOR feedforward loop promoting proliferation.

   Evidence Co-IP for GRN binding, transgenic mouse and xenograft models, western blot of AKT/mTOR components

   PMID:33323378 PMID:33340561

   Open questions at the time

   • Structural basis of FAM135B-GRN binding unknown
   • How FAM135B couples GRN to AKT/mTOR mechanistically not resolved
   • Single lab
5. 2022 High

   Mechanistically embedded FAM135B in the DNA damage response by showing it sustains pre-assembled TIP60-ATM complexes and promotes both HR and NHEJ repair.

   Evidence Co-IP, PLA, GST pull-down, acetyltransferase activity assay, γH2AX/53BP1 foci imaging, comet assay, transgenic and xenograft models

   PMID:35979619

   Open questions at the time

   • Trigger and mechanism for damage-induced release of FAM135B from TIP60 not defined
   • How a single factor promotes both HR and NHEJ unresolved
6. 2024 Medium

   Extended FAM135B function to invasion/EMT through TNIK-Wnt/β-catenin signaling and identified METTL3/m6A as an upstream activator of its expression.

   Evidence Co-IP for TNIK, siRNA epistasis, migration/invasion and lung metastasis assays, m6A modification analysis

   PMID:38881420

   Open questions at the time

   • How FAM135B-TNIK binding activates Wnt signaling mechanistically unclear
   • m6A site(s) on FAM135B transcript not mapped
7. 2024 Medium

   Connected FAM135B to splicing control of DNA repair, showing it drives nuclear SRSF1 translocation via SRPK1 to alter FAAP20 splicing and activate the FA pathway, conferring chemoresistance.

   Evidence Interaction assays for FAM135B-SRPK1-SRSF1, exon-inclusion and FA pathway activation assays, oxaliplatin chemosensitivity assays in colorectal cancer cells

   PMID:39397154

   Open questions at the time

   • Direct versus indirect nature of FAM135B-SRPK1 interaction not fully resolved
   • Whether this splicing role operates outside colorectal cancer untested
8. 2026 Medium

   Identified FAM135B as a positive regulator of innate immune signaling by stabilizing IFI16 against TRIM21-mediated degradation to activate STING.

   Evidence Co-IP, competitive binding assay, ubiquitination assay, site-directed mutagenesis (K143/K561), STING activation and T-cell cytotoxicity assays in triple-negative breast cancer

   PMID:41218197

   Open questions at the time

   • Structural basis of FAM135B-IFI16 versus TRIM21-IFI16 competition not defined
   • Single lab, recently published
9. 2026 Medium

   Showed FAM135B suppresses NF-κB/IL-6-driven angiogenesis by stabilizing and inhibiting the IKK complex, and identified HNF4A as a direct transcriptional driver of FAM135B.

   Evidence Co-IP/MS for IKK complex, western blot of IKKβ/P65, IL-6 ELISA, dual-luciferase HNF4A promoter assay, rescue experiments, orthotopic/subcutaneous xenografts in glioblastoma

   PMID:42260484

   Open questions at the time

   • Mechanism by which binding both stabilizes and inhibits IKK is unresolved
   • Reconciliation of this anti-NF-κB role with pro-tumor roles in other contexts unclear

• It remains unknown whether FAM135B's many context-specific interactions reflect a single unifying biochemical activity (e.g., a generic scaffold) or independent functions, and no structural or domain-level model explains its partner selectivity.
• No structural model of FAM135B
• No defined catalytic or enzymatic activity
• Partner-selectivity determinants unmapped