RPL22L1

RPL22L1 is a ribosomal protein paralog of RPL22 that doubles as a nuclear splicing regulator and, when overexpressed, as a driver of cancer malignancy (PMID:23990801, PMID:28076796). Its expression is held in check by RPL22, which binds an internal hairpin in the RPL22L1 transcript and suppresses its splicing/expression, so that loss of RPL22 triggers compensatory RPL22L1 upregulation and incorporation into ribosomes to support cell growth [PMID:23990801, PMID:bio_10.1101_2024.08.15.608201]. Beyond ribosomes, RPL22L1 carries out an extraribosomal nuclear function by binding smad2 pre-mRNA and promoting inclusion of exon 9, directly antagonizing RPL22-driven exon skipping to tune Nodal/TGF-β signaling and morphogenesis during gastrulation (PMID:28076796). In cancer, RPL22L1 promotes epithelial-to-mesenchymal transition, invasion, proliferation, and drug resistance across multiple tumor types (PMID:26618703, PMID:35973992). Mechanistically it hyperactivates ERK signaling by competitively binding the ERK phosphatase DUSP6 to block ERK dephosphorylation (PMID:40022129), stabilizes Myc protein by inhibiting its ubiquitination within a Myc–RPL22L1 positive feedback loop (PMID:41044601), and engages EGFR/STAT3 signaling to drive temozolomide resistance (PMID:37985768). RPL22L1 is itself a downstream effector of miR-361-5p, which represses it to suppress EMT (PMID:31938372).

1. 2013 High

   Established the regulatory relationship defining RPL22L1's place in ribosome biology: how a paralog's expression is controlled and whether it is functionally interchangeable with RPL22.

   Evidence RNA hairpin binding assay, Rpl22-/- mouse, ribosome fractionation and siRNA rescue

   PMID:23990801

   Open questions at the time

   • Does not define whether RPL22L1-containing ribosomes translate a distinct mRNA subset
   • Mechanism of hairpin recognition not structurally resolved
2. 2017 High

   Revealed that RPL22L1 has an extraribosomal nuclear role, acting as a splicing regulator that antagonizes RPL22 rather than merely substituting for it in ribosomes.

   Evidence Nuclear fractionation, RIP on smad2 intronic sequences, splicing reporters, zebrafish loss-of-function

   PMID:28076796

   Open questions at the time

   • Direct RNA-binding determinants of RPL22L1 not mapped
   • Whether the splicing role extends beyond smad2 unknown
   • Cofactor requirements (cf. RPL22/hnRNP-A1) not defined for RPL22L1
3. 2015 Medium

   Connected RPL22L1 to a cancer phenotype by showing overexpression drives EMT and metastatic behavior, framing it as an oncogenic effector.

   Evidence Overexpression/knockdown, invasion/migration assays, xenograft, EMT-marker Western blots in ovarian cancer

   PMID:26618703

   Open questions at the time

   • No direct molecular target linking RPL22L1 to EMT identified in this study
   • Does not distinguish ribosomal versus extraribosomal contribution
4. 2018 Medium

   Placed RPL22L1 within an upstream regulatory circuit by identifying it as a direct miR-361-5p target whose re-expression rescues EMT suppression.

   Evidence Luciferase 3'UTR reporter, overexpression rescue, invasion/migration and EMT-marker assays in ovarian cancer

   PMID:31938372

   Open questions at the time

   • Single study, single lab
   • Downstream effectors of RPL22L1 in this axis not resolved
5. 2022 Medium

   Began assigning a signaling pathway to RPL22L1's oncogenic action by linking it to ERK activation and sorafenib resistance.

   Evidence Overexpression/knockdown, ERK Western blots, sorafenib + ERK inhibitor drug assays in HCC

   PMID:35973992

   Open questions at the time

   • No direct binding to an ERK-pathway component shown here
   • Pathway placement inferred from inhibitor rescue only
6. 2023 Medium

   Extended the pathway repertoire by implicating EGFR/STAT3 signaling in RPL22L1-driven malignancy and temozolomide resistance.

   Evidence Overexpression/knockdown in GBM, orthotopic/subcutaneous xenografts, STAT3 Western blots, Stattic + TMZ combination

   PMID:37985768

   Open questions at the time

   • No direct biochemical interaction between RPL22L1 and EGFR/STAT3 demonstrated
   • Single lab
7. 2024 Medium

   Refined the RPL22-RPL22L1 control mechanism by showing RPL22 suppresses RPL22L1 at the splicing level and that 28S rRNA sequestration of RPL22 intensifies this repression.

   Evidence Multi-omics, RPL22 frameshift analysis in cancer cell panel, RPL22–28S rRNA/splice-junction interaction studies, rRNA-synthesis perturbation (preprint)

   PMID:bio_10.1101_2024.08.15.608201

   Open questions at the time

   • Preprint, single lab
   • Quantitative contribution of rRNA sequestration versus direct transcript binding unresolved
8. 2025 Medium

   Provided the first direct molecular mechanism for RPL22L1-driven ERK hyperactivation: competitive binding to the phosphatase DUSP6 that blocks ERK dephosphorylation.

   Evidence Co-IP competitive binding with DUSP6, ERK-phosphorylation Western blots, functional assays, xenograft, ERK inhibitor combination in cervical cancer

   PMID:40022129

   Open questions at the time

   • Single lab, no reciprocal/structural validation of the RPL22L1-DUSP6 interface
   • Whether DUSP6 binding accounts for ERK effects in other tumor types not tested
9. 2025 Medium

   Identified a Myc-stabilizing mechanism and a self-reinforcing loop, showing RPL22L1 inhibits Myc ubiquitination while Myc transcriptionally activates RPL22L1.

   Evidence Promoter luciferase reporter, ubiquitination IP, protein-stability assays, functional assays and xenograft in lung adenocarcinoma

   PMID:41044601

   Open questions at the time

   • Direct versus indirect inhibition of Myc ubiquitination not distinguished
   • Single lab, no independent replication

• It remains unresolved how RPL22L1's ribosomal, nuclear splicing, and cytoplasmic signaling activities are mechanistically partitioned and whether they share a common biochemical basis.
• No structure of RPL22L1 or its RNA/protein-binding interfaces
• Whether splicing regulation contributes to its oncogenic phenotypes is untested
• Direct interactors driving STAT3 and EMT phenotypes not biochemically defined