LRP11 is a single-pass type-I membrane protein whose canonical 500-amino-acid isoform has an extracellular MANSC domain, PKD domain and one LDL-receptor class-A module followed by a short cytoplasmic tail. A second cDNA isoform replaces part of the PKD region and lacks the canonical LDLRA module, transmembrane helix and tail; its endogenous protein expression is unknown. LDL-responsive LRP11 signaling has been linked to MAPK13-dependent TCF1 phosphorylation and T-cell proliferation in mouse systems and selected human peripheral-blood lymphocyte assays. In human cervical- and prostate-cancer models, LRP11 perturbation alters proliferation, invasion and beta-catenin-dependent PD-L1 expression, but these disease-context phenotypes do not yet define its normal physiological role. Mouse amygdala Lrp11 abundance increases after experimental stress, without establishing causal roles in individual stress responses.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt's controlled-vocabulary membrane location is consistent with LRP11's curated type-I single-pass topology. Reason: Membrane is broad but correct and represents a constitutive property of the protein rather than a contextual phenotype. The electronic annotation is a direct mapping from the UniProt subcellular-location token SL-0162. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0162 · UniProt membrane subcellular-location vocabulary term SUPPORTS TRANSFER The mapped location agrees with the signal peptide, extracellular domain, transmembrane helix and cytoplasmic tail in the reviewed record. |
| GO:0009408 response to heat | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfers response to heat from mouse Lrp11, where the source row is an IEP from a multi-stressor amygdala expression study. Reason: IEP can support a response annotation, but this human IEA is a second-step orthology transfer from a single mouse-amygdala expression study. The accessible abstract describes generic stress models without identifying heat as an assayed condition, so the term-specific human transfer is too weak and context-bound. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8CB67 · mouse Lrp11 SOURCE WEAK OR INFERRED Current QuickGO traces this term to IEP evidence from PMID:25262641, an amygdala expression-response study. ensembl:ENSMUSP00000019931 · mouse Lrp11 Ensembl protein CIRCULAR OR REDUNDANT This is a second identifier for the same mouse donor, not independent biological evidence. |
| GO:0009409 response to cold | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfers response to cold from mouse Lrp11, where the source row is an IEP from a multi-stressor amygdala expression study. Reason: IEP can support a response annotation, but this human IEA is a second-step orthology transfer from a single mouse-amygdala expression study. The accessible abstract describes generic stress models without identifying cold as an assayed condition, so the term-specific human transfer is too weak and context-bound. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8CB67 · mouse Lrp11 SOURCE WEAK OR INFERRED Current QuickGO traces this term to IEP evidence from PMID:25262641, an amygdala expression-response study. ensembl:ENSMUSP00000019931 · mouse Lrp11 Ensembl protein CIRCULAR OR REDUNDANT This is a second identifier for the same mouse donor, not independent biological evidence. |
| GO:0009414 response to water deprivation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfers response to water deprivation from mouse Lrp11, where the source row is an IEP from a multi-stressor amygdala expression study. Reason: IEP can support a response annotation, but this human IEA is a second-step orthology transfer from a single mouse-amygdala expression study. The accessible abstract describes generic stress models without identifying water deprivation as an assayed condition, so the term-specific human transfer is too weak and context-bound. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8CB67 · mouse Lrp11 SOURCE WEAK OR INFERRED Current QuickGO traces this term to IEP evidence from PMID:25262641, an amygdala expression-response study. ensembl:ENSMUSP00000019931 · mouse Lrp11 Ensembl protein CIRCULAR OR REDUNDANT This is a second identifier for the same mouse donor, not independent biological evidence. |
| GO:0009612 response to mechanical stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfers response to mechanical stimulus from mouse Lrp11, where the source row is an IEP from a multi-stressor amygdala expression study. Reason: IEP can support a response annotation, but this human IEA is a second-step orthology transfer from a single mouse-amygdala expression study. The accessible abstract describes generic stress models without identifying mechanical stimulus as an assayed condition, so the term-specific human transfer is too weak and context-bound. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8CB67 · mouse Lrp11 SOURCE WEAK OR INFERRED Current QuickGO traces this term to IEP evidence from PMID:25262641, an amygdala expression-response study. ensembl:ENSMUSP00000019931 · mouse Lrp11 Ensembl protein CIRCULAR OR REDUNDANT This is a second identifier for the same mouse donor, not independent biological evidence. |
| GO:0033555 multicellular organismal response to stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfers multicellular organismal response to stress from mouse Lrp11, where the source row is an IEP from an amygdala expression study. Reason: IEP can support this response term, but the human IEA is a second-step orthology transfer from one expression survey confined to mouse amygdala. The accessible abstract reports generic stress models without resolving the individual paradigms, so broad organism-level transfer to human LRP11 is too weak and context-bound. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8CB67 · mouse Lrp11 SOURCE WEAK OR INFERRED Current QuickGO traces this term to IEP evidence from PMID:25262641, an amygdala expression-response study. ensembl:ENSMUSP00000019931 · mouse Lrp11 Ensembl protein CIRCULAR OR REDUNDANT This is a second identifier for the same mouse donor, not independent biological evidence. |
| GO:0035902 response to immobilization stress | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfers response to immobilization stress from mouse Lrp11, where the source row is an IEP from an amygdala expression study. Reason: IEP can support a response annotation, but this human IEA is a second-step orthology transfer from a single mouse-amygdala expression study. The accessible abstract describes generic stress models without identifying immobilization as an assayed condition, so the term-specific human transfer is too weak and context-bound. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8CB67 · mouse Lrp11 SOURCE WEAK OR INFERRED Current QuickGO traces this term to IEP evidence from PMID:25262641, an amygdala expression-response study. ensembl:ENSMUSP00000019931 · mouse Lrp11 Ensembl protein CIRCULAR OR REDUNDANT This is a second identifier for the same mouse donor, not independent biological evidence. |
| GO:0042594 response to starvation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfers response to starvation from mouse Lrp11, where the source row is an IEP from a multi-stressor amygdala expression study. Reason: IEP can support a response annotation, but this human IEA is a second-step orthology transfer from a single mouse-amygdala expression study. The accessible abstract describes generic stress models without identifying starvation as an assayed condition, so the term-specific human transfer is too weak and context-bound. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8CB67 · mouse Lrp11 SOURCE WEAK OR INFERRED Current QuickGO traces this term to IEP evidence from PMID:25262641, an amygdala expression-response study. ensembl:ENSMUSP00000019931 · mouse Lrp11 Ensembl protein CIRCULAR OR REDUNDANT This is a second identifier for the same mouse donor, not independent biological evidence. |
| GO:0051219 phosphoprotein binding | IMP PMID:17620599 Functional specialization of beta-arrestin interactions reve... | UNDECIDED | Summary: The cited study is a large beta-arrestin interactome screen, but the cached abstract does not identify LRP11 or establish that its partner was phosphorylated. Reason: The relevant protein list and assay-level evidence are confined to supplementary tables that are not represented in the cached publication. Curator deference is appropriate for this experimental annotation: neither acceptance nor rejection of phosphoprotein binding is justified from the available LRP11-specific evidence. Supporting Evidence: PMID:17620599 As determined by LC tandem MS, 71 proteins interacted with beta-arrestin 1, 164 interacted with beta-arrestin 2, and 102 interacted with both beta-arrestins. |
| GO:0005886 plasma membrane | IC PMID:17620599 Functional specialization of beta-arrestin interactions reve... | ACCEPT | Summary: Although the IC source term has no compartment semantics, independent intact-cell blocking-antibody experiments support an accessible cell-surface pool of LRP11. Reason: The imported IC provenance alone is insufficient, but LRP11 blockade altered LDL-induced responses in intact T cells. Together with type-I membrane topology, these data independently support plasma-membrane localization in the tested T-cell context. Propagation Review Root cause: NO FAILURE CORE Sources checked: GO:0051219 · phosphoprotein binding SOURCE WEAK OR INFERRED This IC source term provides no plasma-membrane semantics, but independent intact-cell antibody perturbations support the location. Supporting Evidence: PMID:38272565 To confirm this finding, we used an LRP11 blocking antibody to block LRP11. The in vitro stimulation assay showed that LRP11 blockade offset LDL-induced proliferation and the frequency of CD8+ T cells (figure 3C,D). |
| GO:0030169 low-density lipoprotein particle binding | ISS PMID:38272565 LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 ph... | NEW | Summary: A mouse Lrp11-ectodomain/CD3e chimeric reporter responded to LDL; this supports LDL recognition but is not a direct biochemical observation of LDL binding. Reason: GO:0030169 is proposed conservatively by exact-ortholog inference from the LDL-responsive ectodomain reporter, while the absence of purified-protein binding data remains explicit. GO:0005041 is not proposed because neither direct binding nor delivery of LDL into the cell by endocytosis was demonstrated. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8CB67 · mouse Lrp11 SUPPORTS TRANSFER Verified PTHR46876:SF1 co-membership with human Q86VZ4 supports the orthology boundary; the ligand assay used a mouse Lrp11 extracellular domain reporter, and human PBMC blocking experiments support conservation of the downstream axis. Supporting Evidence: PMID:38272565 Using a cell-based chimeric receptor screening system, we showed that LRP11 interacted with LDL and activated TCF1. |
| GO:0038023 signaling receptor activity | ISS PMID:38272565 LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 ph... | NEW | Summary: Endogenous mouse Lrp11 knockdown impaired LDL-induced proliferation and Tcf7 expression; LRP11 associated with MAPK13, and antibody/inhibitor perturbations placed LRP11 upstream of MAPK13-dependent TCF1 phosphorylation. Reason: The broad signaling-receptor term captures perturbation-supported signal transduction without inventing a more specific receptor class or endocytic mechanism. Species transfer remains explicit because the proximal shRNA, co-IP and phosphorylation experiments were mouse-dominant, although human PBMC inhibitor studies support conservation of the axis. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8CB67 · mouse Lrp11 SUPPORTS TRANSFER Verified PTHR46876:SF1 co-membership with human Q86VZ4 supports the orthology boundary; mouse ligand/receptor and pathway experiments define the proximal mechanism, and human PBMC inhibitor studies support a conserved signaling role. Supporting Evidence: PMID:38272565 Indeed, knockdown of LRP11 impaired CD8+ T-cell proliferation and Tcf7 expression (figure 3H and online supplemental figure S4B). PMID:38272565 The IP data showed that MAPK13 interacted with LRP11 and TCF1 (figure 5A). PMID:38272565 We found that LDL promoted TCF1 phosphorylation, which was eliminated by LRP11 blocking or MAPK13 inhibition (figure 5I). |
| GO:0042102 positive regulation of T cell proliferation | IMP PMID:38272565 LRP11 promotes stem-like T cells via MAPK13-mediated TCF1 ph... | NEW | Summary: LDL promoted proliferation of human peripheral-blood lymphocytes, and an LRP11 blocking antibody or MAPK13 inhibitor suppressed the response. Reason: Direct perturbation in human cells supports positive regulation of T-cell proliferation in this LDL-responsive experimental context. The annotation does not generalize the result to all tissues or make the cancer-immunotherapy setting a constitutive organismal function. Supporting Evidence: PMID:38272565 We found that LDL can also promote human lymphocyte proliferation, whether it is the proliferation ratio or cell numbers, and this effect can be inhibited by aLRP11 and MAPK13 inhibitors (online supplemental figure S7A–C). |
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Download this section (compressed HTML)Q: Does purified human LRP11 bind native LDL directly, and does ligand engagement cause particle internalization, receptor trafficking, signaling, or a combination of these outcomes?
Q: Which normal human T-cell subset or other tissue uses the LRP11-MAPK13-TCF1 axis, and is that pathway active at physiological LDL concentrations?
Q: Is LRP11 isoform 2 translated and secreted, and can it bind ligand or modulate the canonical membrane isoform?
Q: Does endogenous LRP11 interact directly and phospho-dependently with beta-arrestins, and is a functional pool present at the plasma membrane?
Q: Is the rise of mouse amygdala Lrp11 after stress an adaptive effector response, a downstream marker, or a nonspecific consequence of the stress paradigm?
Experiment: Determine ectodomain binding kinetics for LDL, VLDL, oxidized LDL and HDL, then compare fluorescent-particle uptake, degradation and MAPK13 activation in LRP11-knockout cells rescued with wild-type, ligand-binding-defective and cytoplasmic-tail-mutant human LRP11.
Hypothesis: Human LRP11 binds LDL directly but functions primarily as a signaling receptor rather than an LDL-internalization receptor.
Type: biochemical binding, uptake, and genetic rescue
Experiment: Use CRISPR knockout and wild-type rescue in primary human CD8 T-cell subsets, titrate physiological LDL, and measure MAPK13 activation, TCF1 phosphorylation, lineage-state markers and proliferation with orthogonal antibody-free readouts.
Hypothesis: Endogenous human LRP11 is required for LDL-dependent MAPK13-TCF1 signaling and proliferation in a defined CD8 T-cell subset.
Type: primary-cell genetics and phosphosignaling
Experiment: Quantify isoform-specific RNA and peptides in primary tissues, genome-tag each endogenous isoform, and test secretion, stability, LDL binding and effects on canonical-isoform signaling in matched knockout/rescue cells.
Hypothesis: LRP11 isoform 2 is a secreted extracellular protein that modifies ligand availability or canonical LRP11 signaling.
Type: isoform-resolved proteomics and cell biology
Experiment: Combine endogenous reciprocal coimmunoprecipitation or proximity labeling with phosphatase/phosphosite perturbations, cell-surface biotinylation and compartment-resolved imaging before and after candidate ligand stimulation.
Hypothesis: Beta-arrestin association with LRP11 is direct, phosphorylation-dependent and restricted to a cell-surface receptor pool.
Type: interaction proteomics and spatial cell biology
Experiment: Compare inducible, amygdala-restricted Lrp11 knockout, wild-type rescue and expression-matched controls across individual stress paradigms, measuring both behavioral/physiological responses and the previously reported expression-network targets.
Hypothesis: Stress-induced mouse amygdala Lrp11 expression is downstream of stress rather than required for the stress response.
Type: conditional mouse genetics and stress phenotyping
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