ISLR

ISLR (Meflin) is a secreted/cell-surface leucine-rich-repeat and immunoglobulin-domain protein, originally identified by cDNA cloning as a putative protein-interaction/adhesion molecule (PMID:9325048), that functions as a pleiotropic regulator of stromal and mesenchymal signaling. In the intestinal and tumor stroma it controls two paracrine axes: it promotes BMP signaling in cancer-associated fibroblasts, opposing the BMP inhibitor GREM1 and restraining colorectal cancer hepatic metastasis (PMID:33197448), while as an ETS1-induced secreted factor it inhibits epithelial Hippo signaling to activate YAP, driving intestinal regeneration and tumorigenesis (PMID:32128839). ISLR also acts through direct protein partners to control protein turnover and signaling: it mediates ubiquitin-independent proteasomal degradation of insulin receptor alpha via interaction with the proteasome subunit Psma4, thereby limiting insulin sensitivity (PMID:37116777), and binds and promotes degradation of SPARC to license p-ERK1/2-dependent asymmetric division of muscle satellite cells (PMID:38597911). As a redox sensor, ISLR perceives ROS through cysteine 19 and undergoes autophagy-lysosomal degradation, relieving its suppression of PKM2 tetramerization and thereby enhancing glycolysis and antioxidant capacity (PMID:38786060). Additional interactions with CD74 modulate MIF/CD74 immune signaling and CD8+ T-cell infiltration (PMID:40517736). Across cancer cell models ISLR has been linked to proliferation, EMT, and migration through IL-6/JAK/STAT3 and EMT programs (PMID:34713300).

1. 1997 Medium

   Established ISLR as a distinct gene product with a defined domain architecture, framing it as a candidate protein-interaction or adhesion molecule.

   Evidence cDNA cloning, domain analysis, and chromosomal mapping to 15q23-q24

   PMID:9325048

   Open questions at the time

   • No functional assay or binding partner identified
   • Cellular localization of the protein not determined
2. 1999 Medium

   Defined the gene's transcript structure and tissue expression, showing two isoforms encoding an identical protein and ortholog expression in retinal neurons.

   Evidence cDNA library screening, genomic sequencing, and in situ hybridization in mouse

   PMID:10512678

   Open questions at the time

   • Functional role in retina not tested
   • No mechanism linking expression to phenotype
3. 2020 High

   Showed that stromal ISLR shapes epithelial fate through two paracrine pathways — promoting BMP signaling against GREM1 to restrain CRC metastasis, and inhibiting Hippo to activate YAP for intestinal regeneration.

   Evidence Mouse CRC hepatic metastasis and intestinal regeneration models, conditional knockout, AAV8 delivery, tumoroids, and pathway epistasis

   PMID:32128839 PMID:33197448

   Open questions at the time

   • Molecular receptor/binding mechanism by which secreted ISLR alters BMP or Hippo signaling not defined
   • How a single protein produces opposing pro- and anti-tumor effects across contexts unresolved
4. 2020 Medium

   Implicated ISLR in skeletal muscle homeostasis via IGF1-PI3K/Akt-FOXO signaling controlling atrophy programs.

   Evidence siRNA knockdown and overexpression in myoblasts with dexamethasone atrophy model and Western blot

   PMID:32696215

   Open questions at the time

   • No in vivo validation
   • Direct molecular target in the pathway not identified
5. 2021 Medium

   Linked ISLR to NSCLC tumor progression and glycolysis through the IL-6/JAK/STAT3 pathway.

   Evidence siRNA knockdown, overexpression, GSEA, and IL-6 pathway-activator rescue in NSCLC cells

   PMID:34713300

   Open questions at the time

   • Mechanism connecting ISLR to STAT3 activation not defined
   • Cell-line only, no in vivo confirmation
6. 2022 Medium

   Identified an intracellular partner (Ndufs2) and a role as a brake on IL-6-driven thermogenesis in brown adipose tissue.

   Evidence Islr knockout mouse, protein interaction assay, and metabolic/thermogenesis measurements

   PMID:36077405

   Open questions at the time

   • Direct vs indirect nature of Ndufs2 interaction not resolved
   • Single study
7. 2023 High

   Defined a direct mechanism for ISLR in metabolism: it interacts with the proteasome subunit Psma4 to drive ubiquitin-independent degradation of insulin receptor alpha, limiting insulin sensitivity.

   Evidence Co-immunoprecipitation, Islr knockout mouse, adipose siRNA knockdown, and metabolic assays

   PMID:37116777

   Open questions at the time

   • Structural basis of Psma4 recognition and substrate hand-off not defined
   • Whether the same mechanism operates outside adipocytes unknown
8. 2023 Medium

   Identified MGAT5 as an ISLR partner mediating its pro-tumor effects in gastric cancer.

   Evidence Co-immunoprecipitation, siRNA knockdown, and MGAT5 overexpression rescue in gastric cancer cells

   PMID:37427332

   Open questions at the time

   • Functional consequence of the interaction at the molecular level unclear
   • No reciprocal validation or in vivo test
9. 2024 Medium

   Showed ISLR controls muscle satellite cell fate by binding and degrading SPARC to enable p-ERK1/2-dependent asymmetric division.

   Evidence Islr conditional knockout, SPARC binding assay, p-ERK1/2 Western blot, and muscle regeneration assays

   PMID:38597911

   Open questions at the time

   • Mechanism of SPARC degradation not defined
   • Single lab
10. 2024 Medium

    Established ISLR as a ROS sensor whose cysteine-19-dependent autophagic degradation relieves suppression of PKM2 tetramerization, coupling redox state to glycolysis.

    Evidence ROS stimulation, C19 cysteine mutagenesis, autophagy-lysosome inhibition, and PKM2 activity/tetramerization assays

    PMID:38786060

    Open questions at the time

    • Direct vs indirect effect on PKM2 not fully resolved
    • Single study
11. 2025 Medium

    Connected ISLR to tumor immune evasion via direct CD74 interaction modulating MIF/CD74 signaling and CD8+ T-cell infiltration.

    Evidence Co-immunoprecipitation, knockdown/overexpression, cytokine assays, and TNBC xenograft with radiotherapy and PD-1 blockade

    PMID:40517736

    Open questions at the time

    • Mechanism by which ISLR regulates CD74 transcriptional activity undefined
    • Limited mechanistic dissection

• How a single secreted LRR-Ig protein engages such diverse, often opposing partners (BMP/GREM1, YAP, Psma4, SPARC, PKM2, CD74) through a unified biochemical activity remains unresolved.
• No structural model linking domain architecture to its multiple interactions
• Whether secreted and intracellular pools represent distinct functional forms unknown