IPO11

IPO11 (Importin-11) functions as a nuclear import receptor that delivers specific cargo proteins into the nucleus to control transcriptional and DNA-damage signaling programs (PMID:31881079). In APC-mutant colorectal cancer cells with high Wnt activity, IPO11 is required for nuclear import of β-catenin; its loss reduces nuclear β-catenin and dampens β-catenin target gene activation, sustaining the proliferative Wnt transcriptional program (PMID:31881079). IPO11 also mediates the irradiation-induced nuclear translocation of RPRM, which depends on CDK4/6 phosphorylation of RPRM at serine 98; once nuclear, RPRM binds ATM and promotes its nuclear export and proteasomal degradation, thereby downregulating ATM and impairing DNA repair (PMID:36185355). Beyond these two cargo relationships, no further mechanistic detail on IPO11 has been characterized in the available corpus.

1. 2020 High

   Established IPO11 as the nuclear import factor required to sustain β-catenin-driven Wnt transcription in APC-mutant cancer, identifying a previously unknown node controlling oncogenic Wnt signaling.

   Evidence Genome-wide CRISPR screen with IPO11 knockout, nuclear fractionation/western blot for β-catenin, target gene expression, and patient-derived CRC organoid proliferation assays

   PMID:31881079

   Open questions at the time

   • No direct biochemical demonstration that IPO11 binds β-catenin or a recognition motif
   • Cargo specificity and breadth beyond β-catenin not defined
   • No structural model of the IPO11–cargo interaction
2. 2022 Medium

   Showed IPO11 imports phospho-RPRM into the nucleus to trigger ATM downregulation, linking IPO11 cargo transport to the DNA damage response and radiosensitivity.

   Evidence IPO11 knockdown/knockout, reciprocal RPRM–ATM co-immunoprecipitation, nuclear fractionation, S98 phosphosite mutagenesis, CDK4/6 inhibitor treatment, and in vitro/in vivo radiosensitivity assays

   PMID:36185355

   Open questions at the time

   • Not independently replicated outside a single lab
   • Direct IPO11–RPRM binding not biochemically reconstituted
   • Mechanism by which IPO11 recognizes phospho-S98 RPRM is unresolved

• Whether IPO11 has a general import recognition mechanism unifying its diverse cargoes remains unknown.
• No consensus cargo-recognition signal identified
• No structural or RanGTP-dependence data in the corpus
• Full cargo repertoire uncharacterized