LRCH1 is a cytoplasmic leucine-rich-repeat and calponin-homology-domain protein that restrains chemokine-guided T-cell migration. Its leucine-rich repeats bind the catalytic DHR-2 region of DOCK8, competing with Cdc42 and reducing DOCK8-dependent Cdc42 activation. Chemokine-induced PKC-alpha phosphorylation of DOCK8 releases it from LRCH1 and permits its recruitment to the leading edge of migrating T cells. Suppression of CXCL12-directed migration has also been observed after LRCH1 manipulation in primary human CD4-positive T cells. LRCH1 associates with DOCK7, although an effect on DOCK7 exchange activity has not been established. Additional studies implicate LRCH1 in LAT signaling and in the restraint of lymphocyte and microglial activation, with much of that evidence confined to engineered immune cells or mouse and rat models. Three splice isoforms are known, but their endogenous functional differences and any direct actin-binding activity of the calponin-homology domain remain unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: LRCH1 has a cytoplasmic pool consistent with its regulation of cytosolic DOCK-family GEF signaling. Reason: The phylogenetic localization agrees with direct experimental cytoplasm annotation and with the soluble LRCH1-DOCK8 regulatory mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002699694 SUPPORTS TRANSFER The LRCH family node supports conserved cytoplasmic localization. UniProtKB:Q9Y2L9 SUPPORTS TRANSFER Self-reference: the target is its own IBD seed, which is expected rather than circular -- its own IMP annotation to this term is one of the descendant evidences behind the IBD. The IBA then asserts the additional claim that the function is inherited rather than lineage-specific. |
| GO:1990869 cellular response to chemokine | IBA GO_REF:0000033 | ACCEPT | Summary: LRCH1 participates in the T-cell response to chemokine stimulation by restraining DOCK8-Cdc42 signaling. Reason: The IBA is consistent with the focused perturbation study PMID:28028151, in which chemokine stimulation regulates LRCH1-DOCK8 separation and T-cell polarization and migration. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2443390 SUPPORTS TRANSFER Mouse Lrch1 directly supports the chemokine-response process. PANTHER:PTN002699694 SUPPORTS TRANSFER The LRCH family node agrees with the target-specific mechanism. UniProtKB:Q9Y2L9 SUPPORTS TRANSFER Self-reference: the target is its own IBD seed, which is expected rather than circular -- its own IMP annotation to this term is one of the descendant evidences behind the IBD. The IBA then asserts the additional claim that the function is inherited rather than lineage-specific. |
| GO:2000405 negative regulation of T cell migration | IBA GO_REF:0000033 | ACCEPT | Summary: LRCH1 negatively regulates chemokine-induced T-cell migration through the DOCK8-Cdc42 module. Reason: The term captures the central cellular consequence shown by Lrch1 gain- and loss-of-function experiments in PMID:28028151 and is mechanistically linked to competition with Cdc42 for DOCK8. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2443390 SUPPORTS TRANSFER Mouse Lrch1 perturbation directly supports negative regulation of T-cell migration. PANTHER:PTN002699694 SUPPORTS TRANSFER The family node agrees with the target-specific migration evidence. UniProtKB:Q9Y2L9 SUPPORTS TRANSFER Self-reference: the target is its own IBD seed, which is expected rather than circular -- its own IMP annotation to this term is one of the descendant evidences behind the IBD. The IBA then asserts the additional claim that the function is inherited rather than lineage-specific. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping supports cytoplasmic LRCH1. Reason: The conservative vocabulary mapping agrees with the experimental cytoplasm annotation and the cytosolic DOCK8 regulatory mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER Exact UniProt vocabulary source for cytoplasmic localization. |
| GO:0005515 protein binding | IPI PMID:24255178 Protein interaction network of the mammalian Hippo pathway r... | MARK AS OVER ANNOTATED | Summary: A Hippo-pathway interaction screen reported LRCH1 contacts with both DOCK8 and DOCK7. Reason: The merged screen partners are distinct Rho-family GEFs, but the study does not establish a shared LRCH1 molecular mechanism for both, and generic protein binding is uninformative. Focused evidence supports DOCK8 inhibition separately. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: A proteome-scale binary-interaction map reported an LRCH1-DOCK8 isoform-2 contact. Reason: The screen corroborates physical association with DOCK8 but does not itself establish GEF inhibition, and GO:0005515 is not an informative activity term. The partner isoform records what was tested, not an LRCH1 isoform-specific role. |
| GO:0005515 protein binding | IPI PMID:29467281 The MYO6 interactome reveals adaptor complexes coordinating ... | KEEP AS NON CORE | Summary: Focused interactome and coimmunoprecipitation experiments support LRCH1 association with DOCK7. Reason: PMID:29467281 directly reports LRCH1 coimmunoprecipitation with DOCK7 and distinguishes LRCH1 from the LRCH3-MYO6 interaction. The association is valid but no DOCK7 regulatory consequence is established, so generic binding is retained as non-core rather than treated as the DOCK8 inhibitory mechanism. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: A variant-sensitive interaction screen reported an LRCH1-DOCK8 contact. Reason: This high-throughput contact is compatible with focused DOCK8 evidence, but it does not define the inhibitory mechanism and generic protein binding is insufficiently informative. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Cell-specific proteome-scale networks reported LRCH1 contacts with DOCK8 and DOCK7. Reason: The merged screen contacts corroborate DOCK-family association but do not show that LRCH1 regulates both GEFs equivalently. Generic protein binding obscures the directly demonstrated DOCK8 GEF-inhibitory mechanism. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | KEEP AS NON CORE | Summary: Endogenous-tagging cell maps reported LRCH1 association with DOCK7. Reason: The endogenous-scale observation supports a DOCK7 contact but does not establish its functional consequence. It is retained as non-core because GO:0005515 is generic and DOCK7 inhibition has not been demonstrated for LRCH1. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Multimodal cell maps reported LRCH1 contacts with DOCK8 and DOCK7. Reason: These screen-level contacts do not establish one shared regulatory activity, and generic protein binding is uninformative. Partner-specific mechanistic conclusions require the focused DOCK8 and DOCK7 studies. |
| GO:0005515 protein binding | IPI PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | MODIFY | Summary: LRCH1 binds DOCK8 and inhibits its guanyl-nucleotide exchange activity toward Cdc42. Reason: PMID:28028151 shows that LRCH1 competes with Cdc42 for DOCK8 binding and reduces DOCK8-dependent Cdc42 activation. GO:1990624 guanyl nucleotide exchange factor inhibitor activity captures this mechanism more precisely than protein binding. Proposed replacements: guanyl nucleotide exchange factor inhibitor activity |
| GO:0005737 cytoplasm | IMP PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | ACCEPT | Summary: LRCH1 has a cytoplasmic distribution in the focused DOCK8-Cdc42 migration study. Reason: The experimental curator's cytoplasm assignment is consistent with the cellular compartment in which LRCH1 sequesters DOCK8 from Cdc42 and with both inferred cytoplasmic annotations. |
| GO:0034260 negative regulation of GTPase activity | IDA PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | MODIFY | Summary: LRCH1 inhibits the DOCK8 guanyl-nucleotide exchange factor rather than inhibiting Cdc42 GTP hydrolysis. Reason: GO:0034260 means reducing GTP hydrolysis by a GTPase, which would not capture the reported mechanism. LRCH1 instead competes with Cdc42 for DOCK8 and reduces DOCK8-mediated nucleotide exchange; GO:1990624 precisely represents the demonstrated molecular activity. Because the replacement is a molecular function, its qualifier must change from involved_in to enables. Proposed replacements: guanyl nucleotide exchange factor inhibitor activity Supporting Evidence: PMID:28028151 Next, we identified that LRCH1 competes with Cdc42 for binding to the catalytic DHR-2 domain of DOCK8 and restricts the GEF activity of DOCK8. PMID:28028151 Using two screening systems, we found that LRCH1 competes with Cdc42 for interaction with DOCK8 and restrains T cell migration. |
| GO:1990869 cellular response to chemokine | IMP PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | ACCEPT | Summary: LRCH1 participates in cellular responses to chemokines that reorganize the DOCK8-Cdc42 migration module. Reason: Chemokine stimulation triggers PKCalpha-dependent DOCK8 phosphorylation, separation from LRCH1, and leading-edge relocalization. The term accurately captures the stimulus-response context without making LRCH1 a chemokine receptor. Supporting Evidence: PMID:28028151 In response to chemokine stimulation, PKCΞ± phosphorylates DOCK8 at its three serine sites, promoting DOCK8 separation from LRCH1 and translocation to the leading edge to guide T cell migration. |
| GO:2000405 negative regulation of T cell migration | IMP PMID:28028151 LRCH1 interferes with DOCK8-Cdc42-induced T cell migration a... | ACCEPT | Summary: LRCH1 negatively regulates chemokine-induced T-cell migration by restraining the DOCK8-Cdc42 module. Reason: Focused gain- and loss-of-function experiments support LRCH1 as a negative regulator of T-cell migration. The EAE phenotypes are downstream mouse disease context and are not required to justify this proximal cellular process. Supporting Evidence: PMID:28028151 Using two screening systems, we found that LRCH1 competes with Cdc42 for interaction with DOCK8 and restrains T cell migration. |
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Download this section (compressed HTML)Q: Does endogenous human LRCH1 inhibit the nucleotide-exchange activity of DOCK7 or other DOCK-C-family GEFs, or is functional inhibition selective for DOCK8?
Suggested experts: Rho GTPase signaling experts, T-cell migration experts
Q: Which LRCH1 residues contact the DOCK8 DHR-2 domain, and how does phosphorylation of DOCK8 at Ser2077, Ser2082, and Ser2087 destabilize that interaction?
Suggested experts: Structural biologists, DOCK-family experts
Q: Does the LRCH1 calponin-homology domain bind actin directly in human cells, and is it required for LRCH1 localization or regulation of chemotaxis?
Suggested experts: Cytoskeleton experts
Q: Are the three endogenous LRCH1 splice isoforms differentially expressed or functionally specialized across human T-cell and NK-cell states?
Suggested experts: Human immunologists, Isoform biology experts
Experiment: Reconstitute nucleotide exchange with purified DOCK8 DHR-2, Cdc42, and full-length LRCH1 or a systematic LRCH1 deletion and point-mutant series. Quantify exchange kinetics and binding, then determine the structure of the inhibitory complex and test interface mutants by rescue in LRCH1-deficient primary human T cells.
Hypothesis: The LRCH1 leucine-rich-repeat region directly inhibits DOCK8 by occupying a Cdc42-interaction surface on its DHR-2 domain.
Type: biochemistry and structural biology
Experiment: Introduce phospho-null and phosphomimetic substitutions at endogenous DOCK8 in primary human CD4-positive T cells, and combine proximity measurements, a Cdc42 activity biosensor, live leading-edge imaging, and CXCL12 chemotaxis assays before and after acute LRCH1 depletion.
Hypothesis: Chemokine-induced DOCK8 phosphorylation is the switch that releases endogenous DOCK8 from LRCH1 and restores localized Cdc42 activation in human T cells.
Type: cell signaling and live-cell imaging
Experiment: Compare purified DOCK7 and DOCK8 DHR-2 exchange reactions in the presence of LRCH1, map partner interfaces in matched human cells, and test whether selectively disrupting each interaction changes Cdc42 activation and chemotaxis.
Hypothesis: LRCH1 association with DOCK7 is biochemical but does not reproduce its inhibitory effect on DOCK8.
Type: comparative biochemistry
Experiment: Use long-read RNA sequencing and isoform-specific proteomics across resting and chemokine-stimulated primary human T-cell and NK-cell subsets, followed by isoform-specific rescue of an LRCH1-null background to compare DOCK8, DOCK7, and LAT association, localization, Cdc42 activation, migration, and cytokine outputs.
Hypothesis: Endogenous LRCH1 isoforms differ in partner preference or immune-cell regulatory activity.
Type: isoform-resolved functional genomics
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The structural interface by which the LRCH1 leucine-rich-repeat region occludes Cdc42 binding to the DOCK8 DHR-2 domain has not been resolved, and the residues that determine inhibition are unknown.
OPEN BIOLOGY MF_DARK
Significance: An interface-level mechanism would distinguish direct catalytic inhibition from sequestration and reveal how DOCK8 phosphorylation promotes dissociation from LRCH1.
Provenance (the field's own admissions):
Gap: LRCH1 co-immunoprecipitates with DOCK7, but it is unknown whether LRCH1 inhibits DOCK7 nucleotide-exchange activity or whether this association has a distinct cellular consequence.
OPEN BIOLOGY MF_DARK
Significance: Resolving this question would determine whether GEF inhibition is selective for DOCK8 or is a broader activity toward DOCK-C-family proteins.
Provenance (the field's own admissions):
Gap: Direct actin binding by the calponin-homology domain of human LRCH1 has not been demonstrated, and the cortical function reported for the single Drosophila LRCH protein has not been resolved among the four human paralogues.
OPEN BIOLOGY MF_DARK
Significance: Direct biochemical evidence is needed before the domain architecture can be interpreted as a cytoskeletal molecular activity of human LRCH1.
Provenance (the field's own admissions):
Gap: The endogenous expression, localization, and partner specificity of the three LRCH1 splice isoforms have not been compared in immune cells.
OPEN BIOLOGY RESIDUAL_SUBGAP
Significance: Isoform-resolved measurements are required to determine whether the DOCK8, DOCK7, and LAT observations apply to all LRCH1 products or to a restricted endogenous isoform.
Gap: It remains unclear whether the DOCK8 and LAT mechanisms operate in the same endogenous human T-cell state and whether the Src/Lck and inflammatory phenotypes observed in other immune contexts reflect the same proximal LRCH1 activity.
OPEN BIOLOGY BP_DARK
Significance: Defining the relationship among these mechanisms would separate a conserved proximal immune-signaling role from cell-type-specific downstream effects.
Provenance (the field's own admissions):
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