LRATD1, historically called FAM84A, is a small cytoplasmic protein with an LRAT-like domain and a peripheral distribution that is enriched away from cell-cell contacts in colorectal-cancer cells. Human LRATD1 can receive an N-terminal Gly2-dependent myristoyl modification from NMT1/2 in HEK293T-cell assays. Exogenous expression increases motility in mouse NIH3T3 fibroblasts, and Ser38 phosphorylation has been associated with altered cell morphology; migration effects vary by cell type. Loss-of-function experiments in human papillary-thyroid-cancer cells also reduce migration and invasion. These data establish a context-dependent relationship to cell morphology and motility, but the molecular activity and normal-tissue physiological role of LRATD1 are unknown. The LRAT-like domain has not been shown to catalyze retinoid or lipid metabolism. Two human isoforms are recorded; isoform 2 replaces most of the annotated LRAT-like domain with an alternative C terminus, and its expression and function have not been characterized.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000902 cell morphogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: LRATD1/FAM84A contributes to changes in cell morphology. Reason: The IBA includes Q96KN4 itself as a source and therefore traces the same target-specific evidence as the PMID:16820875 IMP rather than providing independent conserved-process support. The abstract links Ser38 phosphorylation to morphology in an experimental cell system, but no normal physiological morphogenesis role is established, so the process is retained as contextual non-core biology. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002923247 SUPPORTS TRANSFER The PANTHER node records the phylogenetic assertion but does not supply independent conserved-process evidence beyond the target-source annotation. UniProtKB:Q96KN4 SUPPORTS TRANSFER Q96KN4 is the target itself and traces the same PMID:16820875 evidence as the direct IMP annotation, not an independent donor. |
| GO:0048870 cell motility | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: LRATD1/FAM84A promotes cell motility in an experimental overexpression context. Reason: The IBA includes Q96KN4 itself as a source and thus traces the same PMID:16820875 target evidence rather than independently corroborating it. Exogenous human FAM84A increased motility in heterologous mouse NIH3T3 cells, but normal human physiology is untested, so the broad process is retained as contextual non-core biology. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002923247 SUPPORTS TRANSFER The PANTHER node records the phylogenetic assertion but does not supply independent conserved-process evidence beyond the target-source annotation. UniProtKB:Q96KN4 SUPPORTS TRANSFER Q96KN4 is the target itself and traces the same PMID:16820875 evidence as the direct IMP annotation, not an independent donor. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: LRATD1 is a cytoplasmic protein with enrichment near unattached regions of the cell periphery. Reason: The combined ARBA and UniProt subcellular-location mapping agrees with the curator-reviewed experimental cytoplasm annotation from PMID:16820875. The abstract further describes staining in a subcellular membrane region, which is compatible with a peripheral cytoplasmic pool rather than evidence for an integral membrane location. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026971 SUPPORTS TRANSFER The ARBA source supports the conservative cytoplasmic localization. UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER The UniProt cytoplasm vocabulary mapping agrees with direct localization evidence. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: HuRI screening reported candidate LRATD1 interactions with ARHGEF5 and cytoglobin. Reason: The two HuRI screen contacts (ARHGEF5 and cytoglobin) preserve useful partner provenance, but ARHGEF5 and cytoglobin are functionally unrelated and the generic protein-binding term does not identify a coherent molecular activity. Neither screen contact is promoted to an endogenous mechanism without focused validation. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: A neurodegeneration-focused interaction map reported an LRATD1-ATXN10 candidate interaction. Reason: This systematic interaction-screen hit is retained as assay provenance but does not establish an endogenous LRATD1 mechanism, and GO:0005515 is too generic to represent an informative molecular function. |
| GO:0005737 cytoplasm | EXP PMID:16820875 A gene encoding a family with sequence similarity 84, member... | ACCEPT | Summary: Experimental immunocytochemistry supports cytoplasmic LRATD1 localization near the cell periphery. Reason: PMID:16820875 is available only as an abstract, which reports FAM84A staining in a subcellular membrane region lacking neighboring-cell contact. UniProt curators assigned the broader cytoplasm term from the full study; that experimental judgment is retained without over-specifying a membrane compartment. Supporting Evidence: PMID:16820875 Although immuno-cytochemical staining revealed localization of FAM84A protein in the subcellular membrane region, the staining was limited to the region lacking attachment with neighboring cells. |
| GO:0000902 cell morphogenesis | IMP PMID:16820875 A gene encoding a family with sequence similarity 84, member... | KEEP AS NON CORE | Summary: LRATD1 Ser38 phosphorylation and mutagenesis were linked to altered cell morphology. Reason: The paper abstract directly relates LRATD1 phosphorylation to cell morphology, and the IMP annotation reflects curator access to the detailed mutant experiments. Because the cache is abstract-only, the broad process term is retained with curator deference as contextual non-core evidence rather than second-guessed from incomplete assay detail or generalized to normal physiology. Supporting Evidence: PMID:16820875 In addition, we found that exogenous FAM84A expression increased cell motility in NIH3T3 cells, and that phosphorylation of serine 38 of FAM84A was associated with morphology of cells. |
| GO:0048870 cell motility | IMP PMID:16820875 A gene encoding a family with sequence similarity 84, member... | KEEP AS NON CORE | Summary: Exogenous human LRATD1/FAM84A expression increases NIH3T3-cell motility. Reason: PMID:16820875 explicitly reports increased motility after exogenous FAM84A expression. The result is based on heterologous mouse fibroblasts and does not by itself establish normal human tissue physiology, but it directly supports the broad cell-motility process annotation as contextual non-core biology. Supporting Evidence: PMID:16820875 In addition, we found that exogenous FAM84A expression increased cell motility in NIH3T3 cells, and that phosphorylation of serine 38 of FAM84A was associated with morphology of cells. |
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Download this section (compressed HTML)Q: Does the LRAT-like domain of LRATD1 catalyze any reaction, bind a defined lipid or protein ligand, or instead provide a noncatalytic structural module?
Q: Is endogenous LRATD1 required for morphology or motility in any normal human cell lineage, and how does that function differ from tumor-cell phenotypes?
Q: Does Gly2-dependent N-myristoylation control LRATD1 peripheral localization, partner selection, stability, or motility effects?
Q: Which of the reported ARHGEF5, cytoglobin, and ATXN10 screen contacts are endogenous and functionally relevant, if any?
Q: Is LRATD1 isoform 2 expressed as a stable protein, and does disruption of most of the LRAT-like domain change localization or function?
Experiment: Purify the folded domain and screen retinoid, phospholipid, and acyl-donor panels by orthogonal activity and binding assays, including catalytic-residue candidates and domain-disrupting controls. In parallel, compare endogenous partner proteomes after acute deletion of the domain.
Hypothesis: LRATD1 uses its LRAT-like domain as a noncatalytic interaction module rather than as a retinoid or lipid acyltransferase.
Type: biochemistry and proteomics
Experiment: Introduce an endogenous Gly2-to-Ala mutation and an acute LRATD1 degron in human tumor cells with verified expression. Measure N-myristoylation by N-terminal proteomics, membrane partitioning by fractionation and live-cell imaging, and migration after rescue with wild-type or G2A LRATD1.
Hypothesis: N-myristoylation targets LRATD1 to a peripheral cytoplasmic membrane-associated pool required for its effects on cell motility.
Type: cell biology and chemical proteomics
Experiment: Perform matched endogenous knockout and rescue across normal primary cells and colorectal, thyroid, and liver tumor models, quantifying morphology, adhesion, single-cell migration, invasion, and immediate signaling changes. Use acute degradation to separate primary from transcriptionally secondary effects.
Hypothesis: LRATD1 controls a conserved morphology/motility program only in selected cell states rather than universally.
Type: comparative functional genomics
Experiment: Test endogenous LRATD1 contacts with ARHGEF5, cytoglobin, and ATXN10 using reciprocal affinity purification, proximity labeling, and microscopy, then disrupt each contact by endogenous interface mutation and assess rescue of motility and morphology.
Hypothesis: One or more interaction-screen candidates mediate the LRATD1 motility phenotype.
Type: interaction proteomics
Experiment: Quantify isoform-specific transcripts and unique peptides across normal and tumor tissues, then compare endogenous-locus isoform-1 and isoform-2 rescue for stability, myristoylation, localization, partner proteomes, and cell behavior.
Hypothesis: LRATD1 isoform 2 is a stable, functionally distinct protein because its alternative C terminus disrupts most of the LRAT-like domain.
Type: isoform-resolved proteomics
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The molecular activity of LRATD1 is unknown, including whether its LRAT-like domain has any catalytic or noncatalytic ligand-binding function.
OPEN BIOLOGY MF_DARK
What is known: LRATD1 contains a sequence-classified LRAT-like domain and affects cell morphology and motility in perturbation assays, but no substrate, product, catalytic reaction, or direct regulatory mechanism has been demonstrated. The domain name alone does not establish retinoid acyltransferase or lipid metabolic activity.
Significance: Identifying the molecular activity is necessary to connect the observed cell behaviors to a causal biochemical mechanism and to define any core GO-CAM activity for LRATD1.
What would resolve it: Structure-guided biochemical screening and endogenous interaction analysis, coupled to domain- and active-site-residue perturbation, would distinguish enzymatic, lipid-binding, and adaptor mechanisms.
Provenance (the field's own admissions):
Gap: The normal human physiological process controlled by LRATD1 is unknown.
OPEN BIOLOGY BP_DARK
What is known: Motility and morphology effects have been reproduced in heterologous overexpression and human tumor-cell perturbation systems, but no endogenous requirement has been established in a normal human tissue or organoid.
Significance: This gap prevents tumor-associated migration phenotypes from being interpreted as the normal evolved function of LRATD1.
What would resolve it: Endogenous loss, rescue, and lineage-resolved phenotyping in primary human cells from tissues with verified LRATD1 protein expression would establish its physiological process.
Gap: The functional consequence and endogenous prevalence of LRATD1 N-myristoylation are unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: NMT inhibition and Gly2 mutation abolish chemical-proteomic labeling of overexpressed LRATD1 in HEK293T cells, establishing it as an NMT substrate, but not showing how the modification changes localization or activity.
Significance: Myristoylation could explain the peripheral cytoplasmic localization and context-dependent motility phenotype, but that causal link remains untested.
What would resolve it: Endogenous N-terminal proteomics and wild-type versus G2A rescue experiments should test modification occupancy, membrane association, partner selection, and motility effects.
Provenance (the field's own admissions):
Gap: The expression, localization, molecular activity, and biological effects of LRATD1 isoform 2 are unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Isoform 2 retains Gly2 and Ser38 but replaces residues 146-292, disrupting most of the annotated residues 133-228 LRAT-like domain; published functional studies do not identify which isoform was tested endogenously.
Significance: The large domain-disrupting alternative segment could create substantial isoform-specific behavior, so shared-function assumptions are unsafe.
What would resolve it: Isoform-specific RNA and N-terminal/C-terminal proteomics followed by endogenous-locus isoform rescue would establish expression and functional differences.
Gap: No endogenous molecular partner has been validated for LRATD1.
OPEN BIOLOGY MF_DARK
What is known: Binary screens report ARHGEF5, cytoglobin, and ATXN10 contacts, but these unrelated candidates have not been shown to form endogenous, functional complexes with LRATD1.
Significance: Partner validation may reveal whether LRATD1 is an adaptor or regulator and could connect its peripheral localization to morphology and motility.
What would resolve it: Endogenous reciprocal co-immunoprecipitation, proximity labeling, and interaction-dependent rescue should test the screen candidates and discover context-specific partners without assuming stable-complex membership.
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