RELL2

RELL2 is a TNF receptor-family-associated protein that functions in plasma-membrane-anchored signaling controlling apoptosis, stress-kinase activation, and tumor cell behavior (PMID:16389068, PMID:28688764). It physically associates with the related receptors RELT and RELL1 and co-localizes with them at the plasma membrane (PMID:16389068), and engages the transcription factor MDFIC, which is recruited to the same membrane compartment (PMID:33367115). RELL2 is a substrate of the OSR1/OXSR1 kinase, which binds and phosphorylates it (PMID:16389068), and its overexpression drives activation of the p38 MAPK pathway in a manner dependent on OSR1 and TRAF2 (PMID:28688764) and induces apoptotic cell death (PMID:19969290). RELL2 expression is constrained post-transcriptionally by miR-18a and at the level of intron-4 splicing by the RNA helicase DHX38, and in both breast cancer and pancreatic ductal adenocarcinoma RELL2 acts as an anti-metastatic, anti-proliferative, pro-apoptotic factor whose loss promotes migration and chemoresistance (PMID:30817902, PMID:37506056).

1. 2005 High

   Established RELL2 as a member of a plasma-membrane receptor family by showing it associates with RELT and RELL1 and is a kinase substrate, defining its first molecular partners and a candidate signaling input.

   Evidence Reciprocal in vitro co-immunoprecipitation with fluorescence co-localization, plus yeast two-hybrid and in vitro kinase assay identifying OSR1/OXSR1

   PMID:16389068

   Open questions at the time

   • Functional consequence of OSR1 phosphorylation on RELL2 not defined
   • Phosphorylation site(s) not mapped
   • Interactions shown in vitro/overexpression, not at endogenous levels
2. 2009 Medium

   Linked RELL2 to programmed cell death by showing its overexpression triggers apoptotic morphology and DNA fragmentation, assigning a functional output to the receptor.

   Evidence Transient overexpression in HEK293 with DNA fragmentation assay and morphological analysis

   PMID:19969290

   Open questions at the time

   • Overexpression phenotype may not reflect endogenous physiology
   • Death pathway (caspase dependence, upstream trigger) not delineated
3. 2017 Medium

   Placed RELL2 in a defined signaling cascade by showing it activates p38 MAPK through OSR1 and TRAF2, connecting its membrane partners to a downstream stress-kinase output.

   Evidence Overexpression with dominant-negative OSR1 and TRAF2 constructs and western blotting for p38 activation in HEK293

   PMID:28688764

   Open questions at the time

   • Epistasis based on dominant-negative constructs in overexpression context
   • Endogenous receptor ligand/stimulus driving p38 activation unknown
   • Relationship between p38 activation and the apoptotic phenotype not resolved
4. 2019 Medium

   Identified a post-transcriptional brake on RELL2 and a tumor-suppressive role, showing miR-18a directly silences RELL2 to promote breast cancer migration.

   Evidence Luciferase reporter target validation, siRNA knockdown, qPCR/western, and migration/invasion assays in 4T1 and MDA-MB-231 cells

   PMID:30817902

   Open questions at the time

   • Mechanism by which RELL2 restrains migration not defined
   • Single lab; in vivo metastasis effect not established
5. 2020 Medium

   Extended the RELL2 interactome to the transcription factor MDFIC, raising a possible link between membrane signaling and transcriptional output.

   Evidence Yeast two-hybrid, in vitro co-immunoprecipitation, fluorescence co-localization with deletion-mutant mapping

   PMID:33367115

   Open questions at the time

   • Functional consequence of RELL2–MDFIC interaction unknown
   • Whether MDFIC transcriptional activity is altered by RELL2 not tested
6. 2023 Medium

   Revealed a splicing-level control of RELL2 by DHX38 and reinforced its anti-oncogenic role in pancreatic ductal adenocarcinoma.

   Evidence RIP-qPCR showing direct DHX38–RELL2 pre-mRNA interaction, intron-4 retention analysis, and proliferation/gemcitabine cytotoxicity/apoptosis assays

   PMID:37506056

   Open questions at the time

   • Functional difference between intron-4-retained and spliced RELL2 isoforms not characterized
   • Single lab; mechanism connecting RELL2 to chemosensitivity not resolved

• The physiological ligand/stimulus that activates RELL2 at the cell surface and how its phosphorylation, p38 activation, apoptosis, and tumor-suppressive functions are mechanistically integrated remain unknown.
• No endogenous activating ligand or stimulus identified
• No structural model of RELL2 or its complexes
• Link between phosphorylation state and downstream outputs untested