Cd44

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004888 transmembrane signaling receptor activity	IEA GO_REF:0000118	ACCEPT	Summary: CD44 is a single-pass type I membrane protein that converts extracellular hyaluronan engagement into intracellular signalling. In naked mole-rat cells this is demonstrated directly: an antibody applied to the outside of intact cells changes proliferation and transformation behaviour, which requires the receptor to be transmitting across the membrane. Reason: The TreeGrafter node assertion is confirmed by naked mole-rat data rather than merely inherited. Blocking CD44 on intact naked mole-rat cells raises saturation density and permits anchorage-independent growth, and the authors trace the signal through the cytoplasmic partner NF2/merlin, so the transmembrane signal-transduction step is established for this species. The UniProt record independently supports the topology required by the term (single-pass type I membrane protein, TRANSMEM 609..630), and the cytoplasmic tail through which the signal is relayed is the most conserved segment of the protein (97.2% identity to human). Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000027508 · CD44 ancestral node SUPPORTS TRANSFER Node-level receptor assertion, independently confirmed in the target species by antibody blockade on intact naked mole-rat cells. Supporting Evidence: PMID:23783513 To confirm that HA signaling triggers ECI via the CD44 receptor we cultured naked mole-rat cells in the presence of a CD44-blocking antibody. Naked mole-rat cells grown with CD44 antibodies reached a higher cell density (Figure 3b) indicating that the ECI signal from HMW-HA is in part transmitted via the CD44 receptor. PMID:23783513 On the cytoplasmic face, the CD44 receptor interacts with NF2 (merlin), which mediates contact inhibition17. file:HETGA/Cd44/Cd44-uniprot.txt TRANSMEM 609..630 file:HETGA/Cd44/Cd44-bioinformatics/RESULTS.md The cytoplasmic tail is the single most conserved region (97.2% identity).
GO:0005540 hyaluronic acid binding	IEA GO_REF:0000120	ACCEPT	Summary: The core molecular function. Hyaluronan binding is carried by the N-terminal Link module, and both the sequence evidence and the naked mole-rat functional evidence support it in this species. Reason: Grounded in naked mole rat rather than accepted on the strength of the projection alone. Functionally, a CD44-blocking antibody applied to intact naked mole-rat cells abolishes the hyaluronan-driven growth arrest, and the authors conclude the pathway runs through HA/CD44/NF2; a whole-cell FACS assay shows naked mole-rat cells bind fluorescent hyaluronan about twice as avidly as mouse or human cells (that assay measures the whole cell surface, not CD44 specifically, so it is corroborating rather than decisive). Structurally, all four hyaluronan-contact residues annotated on human CD44 have direct counterparts in the naked mole-rat sequence (R41 to R43, R78 to R80, Y79 to Y81, Y105 to Y107), all six cysteines of the three Link-region disulfides are present, and the Link domain is 92.1% identical to human. The UniProt CAUTION about lacking conserved residues required for feature-annotation propagation comes from the Link-domain rule PROSITE-ProRule PRU00323 and concerns that rule's automatic DISULFID transfer; it is not a finding that the hyaluronan-binding site is degenerate. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P16070 · human CD44 SUPPORTS TRANSFER Human IDA evidence for hyaluronan binding; the binding residues transfer one-to-one to the naked mole-rat sequence. InterPro:IPR000538 · Link domain SUPPORTS TRANSFER Link module present at residues 34-122 and 92.1% identical to human. Supporting Evidence: PMID:23783513 Collectively these results establish that ECI is controlled by the HA/CD44/NF2 pathway. PMID:23783513 Naked mole-rat cells displayed a two-fold higher affinity to HA than mouse or human cells (Figure 3d), which can contribute to higher sensitivity of naked mole rat cells to HA signaling. file:HETGA/Cd44/Cd44-uniprot.txt AltName: Full=Hyaluronate receptor file:HETGA/Cd44/Cd44-bioinformatics/RESULTS.md All four UniProt-annotated hyaluronan-contact residues of human CD44 and all six cysteines forming the three Link-region disulfides have direct counterparts in the NMR sequence
GO:0005576 extracellular region	IEA GO_REF:0000044	MARK AS OVER ANNOTATED	Summary: Derived from the ARBA-propagated UniProt "Secreted" subcellular-location keyword. For a type I membrane protein this location can only mean the shed soluble ectodomain, and shedding is exactly the step that is absent in naked mole-rat fibroblasts. Reason: The keyword is an ARBA family-level propagation, not an observation on this protein. The single direct test of naked mole-rat CD44 ectodomain release found none: ionomycin induced ADAM10-dependent cleavage of CD44 in mouse primary skin fibroblasts but not in naked mole-rat primary skin fibroblasts. This is a genuine species difference and is why the term is downgraded rather than accepted. It is not grounds for REMOVE, because the cause is upstream of CD44 (a phosphatidylserine externalisation deficit) and is rescued by restoring scrambling, so the protein remains a competent substrate; and because only one cell type, one stimulus and one sheddase were tested. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH SOURCE EVIDENCE WEAK Sources checked: UniProtKB-SubCell:SL-0243 · Secreted SOURCE WEAK OR INFERRED ARBA-propagated keyword (ARBA00004613/ARBA00022525) with no observation on the naked mole-rat protein. Supporting Evidence: PMID:36790936 we observed an absence of ADAM10 mediated CD44 cleavage, as well as shedding of exogenous and overexpressed betacellulin in NPSF, whereas in mouse primary skin fibroblasts ionomycin induced ADAM10-dependent cleavage of both CD44 and betacellulin. PMID:36790936 increased phosphatidylserine (PS) externalization, which rescued the ADAM10 sheddase activity and promoted cell migration in NPSF in an ADAM10-dependent manner.
GO:0005886 plasma membrane	IEA GO_REF:0000120	ACCEPT	Summary: The primary site of action. CD44 is a single-pass type I plasma membrane protein and naked mole-rat CD44 is demonstrably accessible to an antibody applied to intact cells. Reason: Supported by three independent strands: the UniProt subcellular-location statement for this entry, the transmembrane helix in its own feature table, and the functional requirement that a cell-impermeant blocking antibody reach the receptor on living naked mole-rat cells. Note that the plasma membrane is not the only compartment in which CD44 acts - a substantial ER pool exists and is captured in a separate proposed annotation - but it is the location at which the hyaluronan-receptor function is exercised. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: file:HETGA/Cd44/Cd44-uniprot.txt SUBCELLULAR LOCATION: Cell membrane PMID:23783513 Similarly, naked mole rat cells cultured in the presence of CD44 blocking antibody formed colonies in soft agar (Supplementary Figure 6).
GO:0005902 microvillus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: ARBA-propagated UniProt subcellular-location term reflecting the ERM-mediated enrichment of CD44 in microvilli described in the wider family. No naked mole-rat evidence either way. Reason: Biologically defensible - the cytoplasmic tail that recruits ERM proteins is 97.2% identical to human, so the mechanism that concentrates CD44 in microvilli is intact - but this is a cell-type-specific surface sub-domain, not where the naked mole-rat hyaluronan-sensing function has been localised. Retained as a peripheral location claim. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:HETGA/Cd44/Cd44-uniprot.txt Cell projection, microvillus
GO:0006954 inflammatory response	IEA GO_REF:0000118	KEEP AS NON CORE	Summary: Ancestral-node assertion reflecting CD44's well-established role in leukocyte trafficking and inflammation in mouse and human. There is no naked mole-rat evidence bearing on it. Reason: The phylogenetic placement is sound and CD44's inflammatory role is deeply conserved, so there is no positive argument for removal. But naked mole-rat immunology is atypical - their immune cell populations lack natural killer cells and they are not broadly disease-resistant - and none of the naked mole-rat CD44 literature addresses inflammation. Kept as a conserved, non-core process claim. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000027508 · CD44 ancestral node SUPPORTS SOURCE BUT NOT TARGET Conserved family process; no naked mole-rat evidence, and the species has an unusual lymphoid compartment. Supporting Evidence: PMID:34476892 These findings are further supported by studies that their immune cell populations lack natural killer cells, the cells responsible for immune surveillance and eradication of virally infected cells (Hilton et al., 2019).
GO:0007155 cell adhesion	IEA GO_REF:0000120	ACCEPT	Summary: CD44 is the canonical hyaluronan adhesion receptor, tethering cells to the hyaluronan of the pericellular matrix. This is the process counterpart of the accepted hyaluronic-acid-binding molecular function. Reason: Supported convergently by the Link domain, the ARBA/UniProt keyword, the ancestral node and the human ortholog, and by the naked mole-rat observation that these cells bind hyaluronan about twice as avidly as mouse or human cells and that a CD44 blockade abolishes the resulting signal. The term is broad, but the more specific alternatives in this branch make claims about cell-cell versus cell-matrix adhesion that the naked mole-rat data do not distinguish, so the general term is the honest level here. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:31036852 The main HA receptor is CD44, a cell surface adhesion receptor that binds a range of ligands and is itself associated with metastasis12. PMID:23783513 Naked mole-rat cells displayed a two-fold higher affinity to HA than mouse or human cells (Figure 3d), which can contribute to higher sensitivity of naked mole rat cells to HA signaling.
GO:0016020 membrane	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO mapping from the CD44_antigen signature. True but maximally uninformative: the specific membrane is known. Reason: The InterPro2GO mapping is deliberately conservative and stops at the root membrane term. The compartment is established for this protein - UniProt records cell membrane, single-pass type I, and a transmembrane helix at 609-630 - so the specific child term should be used. This is a granularity correction, not a challenge to the mapping. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR001231 · CD44_antigen SUPPORTS TRANSFER Signature is correct; only the mapped term is too general. Proposed replacements: plasma membrane Supporting Evidence: file:HETGA/Cd44/Cd44-uniprot.txt SUBCELLULAR LOCATION: Cell membrane
GO:0016192 vesicle-mediated transport	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: A pure GO-to-GO logical inference with no organism evidence: the row exists only because CD44 was annotated to cargo receptor activity. It lands at the top of the transport hierarchy and inherits the weakness of its parent. Reason: Two problems compound. First, the inference chains off GO:0038024 cargo receptor activity, which this review marks over-annotated for the naked mole rat because the hyaluronan-uptake-and-turnover arm of CD44 biology is precisely what this species has dialled down: hyaluronidase activity in naked mole-rat cells is much lower than in human, mouse or guinea pig, and the tissue phenotype is hyaluronan accumulation. Second, even taken at face value the resulting term is a root-level transport grouping that conveys nothing specific about CD44. Not removed, because CD44-mediated hyaluronan endocytosis is real in other mammals and has simply never been assayed in naked mole-rat cells. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH CIRCULAR PROPAGATION Sources checked: GO:0038024 · cargo receptor activity SOURCE WEAK OR INFERRED The only source is another annotation on the same protein; the inference adds no independent evidence and the parent row is itself downgraded here. Supporting Evidence: PMID:23783513 HAase activity of the naked mole-rat cells was much lower than that of human, mouse or guinea pig cells (Figure 2c). PMID:39009271 Naked mole-rats (NMRs) accumulate abundant high-molecular weight hyaluronan (HA) in their tissues, suggesting decreased HA degradation.
GO:0016323 basolateral plasma membrane	IEA GO_REF:0000118	KEEP AS NON CORE	Summary: Ancestral-node assertion of polarised epithelial localisation. Plausible for the family; untested in the naked mole rat. Reason: A polarity-specific sub-compartment claim that applies only in polarised epithelia and has no naked mole-rat support. It sits alongside an apical plasma membrane annotation projected from a different human study, and the two cannot both be the general case; of the pair, the basolateral assignment is the one carried by the phylogenetic node rather than by a single cell-line observation, so it is retained here as non-core while the apical row is marked over-annotated. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH
GO:0019221 cytokine-mediated signaling pathway	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: GO-to-GO inference from the cytokine receptor activity row, which itself reflects CD44's role as the signal-transducing component of the MIF-CD74 receptor complex. The underlying human biology is real; there is no naked mole-rat evidence. Reason: Worth noting a quiet strengthening in the inference: the molecular-function row it derives from carries the qualifier contributes_to, because CD44 does not bind MIF - CD74 does - whereas this inferred process row carries involved_in, converting a contributory role into a participatory one. That said, CD44 is genuinely required for MIF-driven signalling in human cells, and its cytoplasmic tail, the part that does the transducing, is 97.2% identical to human, so the process claim is defensible for the ortholog. Kept as non-core: no naked mole-rat data, and it is a conserved immune signalling role rather than part of this species' hyaluronan or proteostasis biology. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: ROLE CONFLATION Sources checked: GO:0004896 · cytokine receptor activity SOURCE WEAK OR INFERRED Source row is qualified contributes_to; the inferred process row is qualified involved_in. Supporting Evidence: file:HETGA/Cd44/Cd44-bioinformatics/RESULTS.md The cytoplasmic tail is the single most conserved region (97.2% identity).
GO:0032991 protein-containing complex	IEA GO_REF:0000117	MODIFY	Summary: Root-level ARBA rule assertion that CD44 is part of some protein-containing complex. True of most membrane receptors and therefore uninformative. Reason: The essence is sound - CD44 does function within multiprotein assemblies - but the root term states nothing. The only specific complex supported anywhere in this annotation set is the macrophage migration inhibitory factor receptor complex, whose GO definition names CD44 explicitly, so that is the term the assertion should resolve to. A caution worth recording: in naked mole-rat tissue the dominant ligand actively opposes CD44 assembly, since very-high-molecular-mass hyaluronan suppresses CD44 protein-protein interactions where ordinary high-mass hyaluronan promotes them. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00028902 · ARBA rule SOURCE WEAK OR INFERRED Machine-learned rule landing on the complex root term. Proposed replacements: macrophage migration inhibitory factor receptor complex Supporting Evidence: PMID:32398747 These results show that CD44 protein-protein interactions are promoted by HMM-HA but are suppressed by vHMM-HA.
GO:0048731 system development	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: A very high-level developmental grouping term assigned by an ARBA machine-learned rule, with no naked mole-rat evidence and no indication of which system is meant. Reason: The term is so general that it neither informs a reader nor constrains a model: almost any broadly expressed signalling receptor would satisfy it. It rests on a statistical rule rather than on any observation of this protein, and no developmental phenotype has been reported for naked mole-rat CD44. Marked over-annotated rather than removed, since CD44 does participate in development in other mammals and the statement is not false, merely empty. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00027702 · ARBA rule SOURCE WEAK OR INFERRED
GO:0160108 animal gross anatomical part developmental process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: A second, equally high-level ARBA developmental grouping term. It adds nothing beyond the system development row and is subject to the same objection. Reason: A grouping term of this altitude cannot be wrong and cannot be useful. It is machine assigned, has no naked mole-rat support, and duplicates in substance the system development annotation. If a developmental role for naked mole-rat CD44 is ever established it should be recorded at the level of the actual structure involved. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00098139 · ARBA rule SOURCE WEAK OR INFERRED
GO:2000106 regulation of leukocyte apoptotic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: The most specific and best-grounded of the four ARBA rule annotations on this protein. CD44 ligation is a documented survival signal in lymphocytes in other mammals. Reason: Unlike the two developmental ARBA rows, this one names a real and well-characterised family behaviour, so it is retained. It stays non-core because it is a machine rule with no naked mole-rat support, because naked mole-rat lymphoid biology is atypical, and because the survival function that this review does accept for naked mole-rat CD44 is a general anti-apoptotic effect under oxidative and ER stress rather than a leukocyte-restricted one. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: ARBA:ARBA00088582 · ARBA rule SOURCE WEAK OR INFERRED
GO:0004896 cytokine receptor activity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Reflects CD44's role as the signal-transducing component of the CD74-CD44 receptor complex for the cytokine MIF. The contributes_to qualifier is correct, since CD74 is the MIF-binding subunit and CD44 supplies the transduction. Reason: The qualifier makes this a complex-level, not an autonomous, activity claim, which is exactly right for CD44 and is the reason it is retained rather than challenged. It is non-core because the evidence is a single human IDA study of the MIF-CD74-CD44 complex projected across species, and neither MIF signalling nor the CD74-CD44 complex has been examined in the naked mole rat. Note for calibration that this row, the MIF receptor complex row, the ERK row and both p53 rows all trace to that one human paper and are not five independent lines of evidence. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P16070 · human CD44 SUPPORTS SOURCE BUT NOT TARGET Single human IDA on the MIF-CD74-CD44 complex; no naked mole-rat data on MIF signalling.
GO:0009986 cell surface	IEA GO_REF:0000120	ACCEPT	Summary: CD44 is displayed on the outer face of the plasma membrane, where it is accessible to exogenous ligand and to blocking antibodies. Reason: Directly demonstrated in the naked mole rat by function rather than by imaging: a CD44-blocking antibody added to the medium of intact naked mole-rat cells changes their proliferation and transformation behaviour, and fluorescein-labelled hyaluronan binds the surface of intact naked mole-rat cells in a FACS assay. Both require the receptor to be surface-exposed. Propagation Review Root cause: NO FAILURE CORE Supporting Evidence: PMID:23783513 To confirm that HA signaling triggers ECI via the CD44 receptor we cultured naked mole-rat cells in the presence of a CD44-blocking antibody. Naked mole-rat cells grown with CD44 antibodies reached a higher cell density (Figure 3b) indicating that the ECI signal from HMW-HA is in part transmitted via the CD44 receptor.
GO:0016324 apical plasma membrane	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Ensembl Compara projection of a single human IDA obtained in a podoplanin-driven directional-migration system. It sits in direct tension with the basolateral plasma membrane annotation on the same protein. Reason: A polarity assignment is a strong, mutually exclusive claim about a given epithelium, and this protein carries both apical and basolateral annotations from different sources. The apical one derives from one human study in a specific migratory context; the basolateral one is the assertion carried by the phylogenetic node. With no naked mole-rat localisation data to arbitrate, promoting a single context-specific human observation to a general localisation for this species overstates what is known. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:P16070 · human CD44 SUPPORTS SOURCE BUT NOT TARGET Single human IDA in a podoplanin/directional-migration system; conflicts with the basolateral node assertion.
GO:0016477 cell migration	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Projected from human, where CD44 promotes migration. In the naked mole rat the shedding step that normally couples CD44 to migration is not engaged, but the capacity is intact. Reason: This is a case where the species difference is quantitative and refines rather than abolishes the annotation. Naked mole-rat primary skin fibroblasts show no ADAM10-dependent CD44 cleavage under a stimulus that produces it in mouse fibroblasts, and restoring phosphatidylserine externalisation rescues both the sheddase activity and migration in an ADAM10-dependent manner - so the CD44-shedding-to-migration axis exists in these cells but is not normally engaged. Retained as non-core rather than accepted or removed. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: PMID:36790936 increased phosphatidylserine (PS) externalization, which rescued the ADAM10 sheddase activity and promoted cell migration in NPSF in an ADAM10-dependent manner.
GO:0030214 hyaluronan catabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Projected from human, where CD44 is the receptor that routes hyaluronan to HYAL1 and HYAL2 for degradation. The naked mole rat is defined by the opposite phenotype - hyaluronan accumulation through reduced degradation. Reason: CD44 has no intrinsic catabolic activity; the human annotation records an upstream contribution, the receptor delivering substrate to hyaluronidases. That contribution is exactly the arm the naked mole rat has attenuated. Hyaluronidase activity is much lower in naked mole-rat cells than in human, mouse or guinea pig cells; naked mole-rat TMEM2 carries Asn247/Val302 in place of the catalytic residues and is inactive; and the tissue phenotype is accumulation of very-high-mass hyaluronan. Reinforcing this, the very-high-mass hyaluronan of this species suppresses CD44 protein-protein interactions rather than promoting the receptor clustering that drives uptake. Marked over-annotated rather than removed because no one has directly assayed CD44-dependent hyaluronan internalisation in naked mole-rat cells. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE ROLE CONFLATION Sources checked: UniProtKB:P16070 · human CD44 SUPPORTS SOURCE BUT NOT TARGET Human IDA/IMP evidence is sound, but naked mole-rat hyaluronan turnover is specifically slowed at several steps. Supporting Evidence: PMID:23783513 HAase activity of the naked mole-rat cells was much lower than that of human, mouse or guinea pig cells (Figure 2c). PMID:39009271 Naked mole-rats (NMRs) accumulate abundant high-molecular weight hyaluronan (HA) in their tissues, suggesting decreased HA degradation. PMID:32398747 These results show that CD44 protein-protein interactions are promoted by HMM-HA but are suppressed by vHMM-HA.
GO:0031258 lamellipodium membrane	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Projected from a human study of podoplanin-driven directional migration. CD44 redistributes to the leading edge on ligation in other mammals; not examined in the naked mole rat. Reason: A transient, migration-state-specific sub-compartment of the plasma membrane rather than a general localisation. The mechanism that would place CD44 there - cytoplasmic tail coupling to the actin machinery - is intact in this species, so the claim is plausible; but it describes a condition, not a resting location, and there is no naked mole-rat evidence. Retained as non-core. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH
GO:0034116 positive regulation of heterotypic cell-cell adhesion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Projected from a human IMP obtained in a renal disease model - BMP-7 modulation of proximal tubular cell to monocyte interaction. An organ-physiology transfer with no naked mole-rat counterpart. Reason: This is the classic weak projection: a term generated in one tissue, in one species, in a disease model, carried across to an animal whose physiology is exactly what differs. The naked mole-rat literature contains nothing on CD44 and monocyte or tubular-cell adhesion, and this species' unusual immune cell composition makes the leukocyte-adhesion context particularly uncertain. Not removed - CD44-hyaluronan interactions genuinely can bridge cells of different types - but the specific positive-regulation claim is not supportable here. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P16070 · human CD44 SUPPORTS SOURCE BUT NOT TARGET Human IMP in a renal proximal-tubule and monocyte disease model. Supporting Evidence: PMID:34476892 These findings are further supported by studies that their immune cell populations lack natural killer cells, the cells responsible for immune surveillance and eradication of virally infected cells (Hilton et al., 2019).
GO:0035692 macrophage migration inhibitory factor receptor complex	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: The GO definition of this complex names CD44 and CD74 explicitly, so the term is CD44-specific and transfers cleanly to an ortholog. There is no naked mole-rat evidence for the complex. Reason: Because CD44 is written into the term's definition, this is one of the more secure projections in the set - the transfer only requires that the naked mole rat has CD74 and MIF, which is likely but unverified here. It is non-core because it rests on a single human IDA and describes immune cytokine signalling rather than the hyaluronan or proteostasis biology that defines this protein's role in the naked mole rat. It is also the specific complex that the root-level protein-containing complex row should resolve to. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P16070 · human CD44 SUPPORTS TRANSFER Term definition names CD44 as a constituent, so orthology transfer is well-defined; membership untested in naked mole rat.
GO:0038023 signaling receptor activity	IEA GO_REF:0000107	MODIFY	Summary: True but one step broader than necessary: the specific child term, transmembrane signaling receptor activity, is already annotated from the phylogenetic node and is what the naked mole-rat evidence supports. Reason: CD44 does receive signals and relay them, so the essence is sound and the human IDA behind the projection is not in question. But the protein's topology is known - single pass, type I, transmembrane helix 609-630 - and the naked mole-rat blocking-antibody experiment demonstrates transmission specifically across the membrane, so the transmembrane child is the correct level of specificity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: transmembrane signaling receptor activity Supporting Evidence: file:HETGA/Cd44/Cd44-uniprot.txt TRANSMEM 609..630
GO:0038024 cargo receptor activity	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Projected from human work showing that CD44 acylation and raft association are needed for receptor and hyaluronan endocytosis. Two objections apply in the naked mole rat - one about the term, one about the species. Reason: On the term: GO:0038024 is defined as binding cargo and recruiting it to nascent vesicles through simultaneous engagement of cargo and coat adaptors. CD44 is an endocytic receptor for hyaluronan, and no coat-adaptor coupling has been demonstrated for it, so the fit is loose even in human. On the species: hyaluronan uptake and turnover is the arm of CD44 biology that the naked mole rat has attenuated - hyaluronidase activity in naked mole-rat cells is much lower than in human, mouse or guinea pig cells, tissues accumulate very-high-mass hyaluronan, and that very-high-mass hyaluronan suppresses rather than promotes the CD44 clustering on which receptor internalisation depends. No CD44-dependent uptake assay has been run in naked mole-rat cells, so the row is downgraded, not removed. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION FUNCTIONAL DIVERGENCE Sources checked: UniProtKB:P16070 · human CD44 SUPPORTS SOURCE BUT NOT TARGET Human endocytosis evidence is sound; the coat-adaptor sense of the term and the naked mole-rat hyaluronan-turnover phenotype both argue against the transfer. Supporting Evidence: PMID:23783513 HAase activity of the naked mole-rat cells was much lower than that of human, mouse or guinea pig cells (Figure 2c). PMID:32398747 These results show that CD44 protein-protein interactions are promoted by HMM-HA but are suppressed by vHMM-HA.
GO:0042110 T cell activation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Projected from human, where CD44 is a long-established T-cell co-stimulatory molecule and memory-cell marker. No naked mole-rat evidence. Reason: One of the best-established roles of CD44 across mammals, so there is no positive argument against it and it is retained. It is non-core here because it belongs to the conserved immunological repertoire of the protein rather than to the naked mole-rat hyaluronan or proteostasis biology, and because naked mole-rat lymphoid biology has not been examined in this respect. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH
GO:0043066 negative regulation of apoptotic process	IEA GO_REF:0000107	ACCEPT	Summary: Unusually well supported for a projected row: CD44 is cytoprotective in two independent naked-mole-rat-centred experimental systems, one against oxidative stress and one against ER stress. Reason: Two lines of evidence converge. First, the cytoprotective effect of naked mole-rat very-high-molecular-mass hyaluronan against oxidative-stress-induced cell death is abolished by CD44 siRNA and by a CD44 neutralising antibody but not by RHAMM knockdown, identifying CD44 as the receptor responsible (that experiment reads naked mole-rat hyaluronan on human fibroblasts, so it establishes the receptor requirement rather than a naked-mole-rat-specific receptor property). Second, and directly on this species' protein, CD44 knockdown in naked mole-rat oligodendrocyte progenitors reduces survival under tunicamycin, and overexpression of naked mole-rat CD44 increases it. Survival signalling is therefore a genuine, species-supported function rather than an inherited assumption. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P16070 · human CD44 SUPPORTS TRANSFER Projection independently confirmed by loss- and gain-of-function on naked mole-rat CD44 in naked mole-rat cells. Supporting Evidence: PMID:32398747 Knockdown of RHAMM did not block the cytoprotective effect of NSF-HA, whereas CD44 siRNA as well as a CD44 neutralizing antibody abrogated its effect PMID:37708026 Indeed, NMR OPCs showed higher resistance against an ER stress inducer, tunicamycin, compared with mouse OPCs in a manner dependent on CD44. PMID:37708026 In addition, overexpression of mouse or NMR CD44 enhanced tunicamycin resistance in mouse OPCs (Figures 3J and 3K).
GO:0043518 negative regulation of DNA damage response, signal transduction by p53 class mediator	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Projected from the single human MIF-CD74-CD44 IDA study. There is convergent but indirect naked-mole-rat-context support: hyaluronan-CD44 signalling modulates p53 target gene output. Reason: Retained because independent work in the naked mole-rat hyaluronan field points the same way - very-high-mass hyaluronan binding CD44 reduces CD44's association with other proteins and partially attenuates p53 and its target genes. But that support is indirect: the effect runs through altered expression of p53 regulators and interactors rather than through direct inhibition of the DNA-damage-activated p53 cascade that this term denotes, and the experiments were done on human fibroblasts with naked mole-rat hyaluronan. Kept as non-core rather than accepted. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P16070 · human CD44 SUPPORTS SOURCE BUT NOT TARGET One of five rows tracing to the same human IDA study; naked mole-rat support is indirect. Supporting Evidence: PMID:33846452 very-HMW HA molecules (> 6 MDa) bind CD44 and thus reduce the binding of CD44 with other proteins, leading to a partial attenuation of p53 and its target genes
GO:0044319 wound healing, spreading of cells	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Projected from a human IMP in a podoplanin-driven directional-migration assay. Naked mole-rat hyaluronan is associated with accelerated wound healing at the organism level, but no CD44 role has been demonstrated in that species. Reason: Plausible in this species by association - reviews of naked mole-rat hyaluronan attribute accelerated wound healing among other advantages to CD44 signalling - but that is a review-level statement, not a demonstration, and the underlying experiment is a single human migration assay. The related consideration that CD44 shedding is not engaged in naked mole-rat fibroblasts also argues against treating cell-spreading behaviour as a core function here. Retained as non-core. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: PMID:38158036 resistance to conditions such as cancer and arthritis, largely attributable to CD44 signaling and other intricate mechanisms
GO:0044344 cellular response to fibroblast growth factor stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Projected from a human IDA in a fibrosarcoma cell line, where bFGF altered hyaluronan synthase and hyaluronidase expression and migration. CD44's role there is as part of the hyaluronan system being modulated, not as an established FGF responder. Reason: The source observation is a transcriptional response of the hyaluronan machinery to bFGF in a tumour cell line; it is a weak basis for asserting that CD44 itself is involved in the cellular response to FGF. The one point in its favour is architectural: the naked mole-rat reference protein is a variant-exon-containing model, and in human CD44 it is the variant region that carries the heparan sulfate able to present growth factors. But that is a statement of capability, not evidence, and nothing is known about which CD44 isoforms naked mole rats express or whether the naked mole-rat protein is glycanated in that way. Downgraded rather than removed. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P16070 · human CD44 SOURCE WEAK OR INFERRED Human IDA is a bFGF-driven expression change in a fibrosarcoma line, not a demonstration that CD44 mediates an FGF response. Supporting Evidence: file:HETGA/Cd44/Cd44-bioinformatics/RESULTS.md The reference protein is a variant-exon-containing (CD44v-like) gene model, not CD44s.
GO:0045121 membrane raft	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Projected from human work showing that CD44 acylation and lipid-raft partitioning are required for its endocytic function. The acylation-competent juxtamembrane and cytoplasmic region is highly conserved in the naked mole rat. Reason: Mechanistically well-founded for the family and structurally plausible here, since the cytoplasmic region carrying the modification is 97.2% identical to human. It is kept non-core because the human evidence ties raft residency specifically to hyaluronan endocytosis, the arm of CD44 biology that this review finds least supported in the naked mole rat, and because no naked mole-rat membrane-fractionation data exist. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Supporting Evidence: file:HETGA/Cd44/Cd44-bioinformatics/RESULTS.md The cytoplasmic tail is the single most conserved region (97.2% identity).
GO:0051132 NK T cell activation	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Projected from a human IDA in which galectin-9 promoted natural killer cell activity through CD44. Two independent problems make this the weakest immunological row in the set. Reason: First, a term-scoping problem at the source, which I checked rather than assumed: I fetched and read the full text of the source publication, and it concerns natural killer cells throughout, including a section demonstrating the galectin-9-CD44 interaction in human NK cells; the strings NKT and natural killer T do not occur in it at all, whereas GO:0051132 is defined for natural killer T cells, a distinct lineage. Second, and independently, naked mole-rat immune cell populations lack natural killer cells altogether, so NK-lineage biology transfers poorly to this species, and whether naked mole rats have a normal NKT compartment is addressed in no cached source. The row is downgraded rather than removed because fixing the source term is a GOA-side question about the human annotation, and because no one has shown that naked mole rats lack NKT cells. Propagation Review Root cause: SOURCE BAD Failure modes: SOURCE MISCITATION LINEAGE OR TAXON MISMATCH Sources checked: UniProtKB:P16070 · human CD44 SOURCE BAD Source publication studies natural killer cells; the term denotes natural killer T cells, which the paper never mentions. Supporting Evidence: PMID:37006235 To determine whether our observations in mice were applicable to humans, we investigated the interaction of CD44 with Gal-9 in human NK cells. PMID:34476892 These findings are further supported by studies that their immune cell populations lack natural killer cells, the cells responsible for immune surveillance and eradication of virally infected cells (Hilton et al., 2019).
GO:0051216 cartilage development	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Projected from a human IEP - an expression-pattern correlation during chondrogenesis, the weakest experimental evidence code. Naked mole-rat cartilage is genuinely unusual, but the published explanation does not involve CD44. Reason: An IEP records that CD44 expression changes during chondrogenesis, which does not establish that CD44 participates in cartilage development; carrying that across species compounds a weak inference with an untested one. The naked mole rat would have been the place to rescue it, since these animals are extremely resistant to post-traumatic osteoarthritis and their cartilage is rich in very-high-mass hyaluronan, but that work attributes the protection to hyaluronan polymer size and cartilage mechanics and does not implicate CD44. Downgraded rather than removed. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P16070 · human CD44 SOURCE WEAK OR INFERRED Source is an IEP expression-pattern correlation during chondrogenesis, not a functional demonstration.
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Conserved downstream signalling output of CD44, projected from the human MIF-CD74-CD44 study and reinforced by the ancestral node. No direct naked mole-rat measurement. Reason: ERK activation is a well-documented CD44 output and the transducing cytoplasmic tail is almost invariant in this species, so the claim is sound at family level. It stays non-core for two reasons: no ERK measurement has been made downstream of naked mole-rat CD44, and the ERK and p38 route was specifically shown to be dispensable for the CD44-dependent ER-stress resistance that is this protein's most distinctive naked-mole-rat-associated function, so it should not be presented as central here. Propagation Review Root cause: NO FAILURE NON CORE Supporting Evidence: PMID:37708026 CD44 modifies proteome and membrane properties of the ER and enhances ER stress resistance in a manner dependent on unfolded protein response regulators without the requirement of HA.
GO:0070487 monocyte aggregation	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Projected from the same human renal disease-model IMP as the heterotypic adhesion row. A narrow, cell-type-specific process with no naked mole-rat counterpart. Reason: The source experiment concerns BMP-7 modulation of proximal tubular cell to monocyte interaction in a human renal system, and the term describes monocytes adhering to one another. Transferring an organ- and leukocyte-specific process of this narrowness to a species whose immune cell composition is documented to be unusual, with no supporting observation, overstates what is known. Not removed, since CD44-hyaluronan interactions do mediate leukocyte adhesion generally. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH
GO:1900625 positive regulation of monocyte aggregation	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: The regulatory counterpart of the monocyte aggregation row, projected from a human IMP in cytokine-stimulated endothelial cells in which the manipulated gene was HAS2. Reason: In the source system the perturbation is of hyaluronan synthesis by endothelial cells; CD44 enters as the monocyte-side receptor for the hyaluronan produced. Attributing positive regulation of monocyte aggregation to CD44 on that basis is already a stretch, and projecting it into a species with an atypical immune cell composition and no relevant data compounds it. Downgraded on the same grounds as the parent process row. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH ROLE CONFLATION
GO:1902166 negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: A deeper form of the p53 claim, from the same single human MIF-CD74-CD44 study. The naked-mole-rat-context support for CD44 attenuating p53 output is indirect but real. Reason: Treated consistently with the broader p53 row: retained, because very-high-mass hyaluronan acting through CD44 partially attenuates p53 and its target genes, and because CD44 demonstrably restrains stress-induced death in naked mole-rat cells; but non-core, because the naked mole-rat evidence concerns p53 target-gene output and oxidative or ER stress rather than the intrinsic apoptotic branch of the DNA-damage response that this term names, and because the projected evidence is one human study. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: SOURCE EVIDENCE WEAK Supporting Evidence: PMID:33846452 very-HMW HA molecules (> 6 MDa) bind CD44 and thus reduce the binding of CD44 with other proteins, leading to a partial attenuation of p53 and its target genes
GO:2000392 regulation of lamellipodium morphogenesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Third row projected from the human podoplanin directional-migration study, alongside lamellipodium membrane and wound-healing cell spreading. Migration-context specific. Reason: Consistent with the treatment of the other two rows from the same source: the cytoskeletal coupling that would let CD44 shape lamellipodia is intact in this species, so the claim is not challenged, but it describes behaviour in a particular migratory state, rests on one human IMP, and has no naked mole-rat support. Note that the naked mole-rat fibroblast data point the other way, with CD44 shedding and the associated migration response not engaged under normal conditions. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH
GO:0005783 endoplasmic reticulum	IDA PMID:37708026 CD44 correlates with longevity and enhances basal ATF6 activ...	NEW	Summary: Proposed new annotation, and the localisation that GOA is missing entirely for this protein. CD44 was shown by immunofluorescence to localise to the ER, including in naked mole-rat oligodendrocyte progenitors, and to co-immunoprecipitate with ER proteins. Reason: Every cellular-component row currently on this protein places it at the cell surface or in the extracellular space. The 2023 study found that CD44 co-localises strongly with three ER markers, that 16 of 41 high-confidence CD44 interactors are ER proteins, and - the point that makes this a naked mole-rat annotation rather than a human one - that naked mole-rat OPCs also show ER localisation of CD44. The functional consequence is demonstrated separately: an ER-retained CD44 ectodomain is sufficient to raise ATF6 target gene expression and tunicamycin resistance, so the ER pool is active and not a biosynthetic intermediate. Supporting Evidence: PMID:37708026 NMR OPCs and U2OS cells also exhibited ER localization of CD44 (Figures S6D and S6E). PMID:37708026 We found that CD44 localizes to the endoplasmic reticulum (ER) and enhances basal ATF6 activity. PMID:37708026 CD44-ectodomain-KDEL enhanced the expressions of HSP90B1 and HSPA5 and cellular resistance to tunicamycin in CD44 KO U2OS cells (Figures 7F and 7G)
GO:1903893 positive regulation of ATF6-mediated unfolded protein response	IMP PMID:37708026 CD44 correlates with longevity and enhances basal ATF6 activ...	NEW	Summary: Proposed new annotation capturing the proteostasis function of CD44. Knockdown of CD44 in naked mole-rat OPCs specifically downregulates ER and ATF6-associated gene sets and reduces ER stress resistance; overexpression of naked mole-rat CD44 increases it. Reason: This is the best-supported CD44 function that the projected GOA set does not represent at all, and it is supported by loss- and gain-of-function on the naked mole-rat protein itself rather than by orthology. ATF6 was the only transcription factor whose targets were enriched among genes downregulated by CD44 knockdown in naked mole-rat OPCs, and the effect on survival is abolished by inhibiting UPR master regulators and is unaffected by supplying hyaluronan, making it mechanistically distinct from the classical hyaluronan-receptor arm. One caveat is recorded rather than hidden: the published effect is on basal ATF6 tone, and the stress-induced UPR is explicitly unchanged, which the available GO term does not distinguish - see proposed_new_terms. Supporting Evidence: PMID:37708026 In the genes that were downregulated by CD44 knockdown, most of the overrepresented terms were associated with the ER, unfolded protein response (UPR)/ER stress, and the UPR regulator ATF6 (Figure 3E). PMID:37708026 In addition, overexpression of mouse or NMR CD44 enhanced tunicamycin resistance in mouse OPCs (Figures 3J and 3K). PMID:37708026 Taken together, CD44 promotes basal ATF6 activity but does not affect UPR gene expressions once exposed to strong ER stress. Knowledge gap: How CD44 raises basal ATF6 output is undetermined. CD44 does not bind ATF6, IRE1 or PERK directly, and the proposed mechanism - altering ER membrane properties - is inferred from an ATF6 point mutant that is blind to membrane lipid changes, not from any measurement of ER lipid composition in CD44-depleted cells. OPEN BIOLOGY MF_DARK "These results suggest that CD44 promotes ATF6 activity by changing the properties of the ER membrane rather than by increasing unfolded proteins in the ER." — PMID:37708026
GO:0008285 negative regulation of cell population proliferation	IMP PMID:23783513 High-molecular-mass hyaluronan mediates the cancer resistanc...	NEW	Summary: Proposed new annotation for the naked mole rat's best-known CD44 phenotype: blocking CD44 on intact naked mole-rat cells lets them reach a higher density and lets them form colonies in soft agar. Reason: This is the outcome that made naked mole-rat CD44 interesting in the first place, and no term in the projected set expresses it. Antibody blockade of CD44 - a specific protein inhibitor, hence IMP - relieves the hyaluronan-driven proliferative arrest, and the authors place CD44 in a defined HA/CD44/NF2 axis. I deliberately chose the general proliferation term rather than a contact-inhibition term: the naked mole-rat arrest is driven by hyaluronan secreted into the medium and acts before confluence, whereas the ontology's contact-inhibition branch requires density information received by direct cell-cell contact, which the naked mole-rat literature explicitly says is not what is happening here. Supporting Evidence: PMID:23783513 To confirm that HA signaling triggers ECI via the CD44 receptor we cultured naked mole-rat cells in the presence of a CD44-blocking antibody. Naked mole-rat cells grown with CD44 antibodies reached a higher cell density (Figure 3b) indicating that the ECI signal from HMW-HA is in part transmitted via the CD44 receptor. PMID:23783513 Collectively these results establish that ECI is controlled by the HA/CD44/NF2 pathway. PMID:34476892 Frequent medium changes remove this hyaluronan and result in confluent cell culture with naked mole‐rat cells attaining higher densities than observed for mouse cells, suggesting that contact inhibition is not a cell autonomous process

Gene Description

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positive regulation of basal ATF6-mediated signalling

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