LRFN4 (SALM3) is a type-I transmembrane cell-adhesion molecule with extracellular leucine-rich-repeat, immunoglobulin-like and fibronectin type-III domains and a cytoplasmic C-terminal ESVV PDZ-binding motif. At postsynaptic membranes, SALM3 engages presynaptic LAR-family receptor phosphatases in a splice-dependent trans-synaptic complex that promotes presynapse differentiation and excitatory synapse development; its cytoplasmic tail associates with PSD-95-family scaffolds and supports postsynaptic-density organization. In human monocytes and macrophages, LRFN4 also signals through 14-3-3, NCK1 and Rac1 to reorganize actin, regulate cell elongation and promote transendothelial migration. SALM3 can associate with other SALMs in cis but, unlike SALM4 and SALM5, does not mediate SALM-SALM homophilic trans-cellular adhesion.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0098839 postsynaptic density membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference places LRFN4/SALM3 at the postsynaptic density membrane, consistent with direct localization of the exact rat Lrfn4 ortholog in postsynaptic-density fractions. Reason: RGD:1585286 is rat Lrfn4/SALM3, not another SALM paralog, and its current annotation record carries direct experimental support for this location from PMID:20410109. The LRFN4-specific PANTHER node and conserved type-I synaptic membrane architecture make this a sound core transfer. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002911882 · LRFN4/SALM3 phylogenetic node SUPPORTS TRANSFER RGD:1585286 · rat Lrfn4/SALM3 SUPPORTS TRANSFER |
| GO:0098978 glutamatergic synapse | IBA GO_REF:0000033 | ACCEPT | Summary: The IBA places LRFN4/SALM3 at glutamatergic synapses using the exact mouse ortholog and an LRFN4-specific phylogenetic node. Reason: MGI:MGI:2385612 is mouse Lrfn4/SALM3. The corresponding rodent evidence shows SALM3 enrichment in synaptic fractions and induction of excitatory presynaptic differentiation, directly supporting this core localization without importing SALM1/SALM2 receptor-organizing roles. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2385612 · mouse Lrfn4/SALM3 SUPPORTS TRANSFER PANTHER:PTN002911882 · LRFN4/SALM3 phylogenetic node SUPPORTS TRANSFER |
| GO:0099151 regulation of postsynaptic density assembly | IBA GO_REF:0000033 | MODIFY | Summary: SALM3 aggregation on dendritic surfaces promotes PSD-95 clustering, so the inferred regulatory process is correct but lacks its experimentally established positive direction. Reason: The exact mouse Lrfn4 donor and LRFN4-specific PANTHER node trace to gene-specific SALM3 evidence from PMID:20410109. GO:0160036 captures the positive effect on postsynaptic-density assembly more precisely than the unsigned parent term and does not transfer SALM1/SALM2 glutamate-receptor functions. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:2385612 · mouse Lrfn4/SALM3 SUPPORTS TRANSFER The donor record traces to SALM3-dependent PSD-95 clustering. PANTHER:PTN002911882 · LRFN4/SALM3 phylogenetic node SUPPORTS TRANSFER Proposed replacements: positive regulation of postsynaptic density assembly |
| GO:0009986 cell surface | IBA GO_REF:0000033 | ACCEPT | Summary: Cell-surface localization is consistent with direct surface localization of mouse Lrfn4 and with LRFN4's signal peptide, extracellular adhesion domains, and single transmembrane helix. Reason: The donor is the exact mouse Lrfn4/SALM3 ortholog and has direct experimental cell-surface evidence. This is a secure transfer of a core localization rather than a family-wide extrapolation. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2385612 · mouse Lrfn4/SALM3 SUPPORTS TRANSFER PANTHER:PTN002911882 · LRFN4/SALM3 phylogenetic node SUPPORTS TRANSFER |
| GO:0099560 synaptic membrane adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: LRFN4/SALM3 is a postsynaptic adhesion molecule that engages presynaptic LAR-family receptor phosphatases in trans. Reason: The IBA sources are restricted to the exact mouse Lrfn4 ortholog and its phylogenetic node. Gene-specific rodent and human ectodomain evidence supports SALM3-LAR-RPTP adhesion, distinct from SALM4 cis inhibition and from SALM1/SALM2 postsynaptic receptor organization. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2385612 · mouse Lrfn4/SALM3 SUPPORTS TRANSFER PANTHER:PTN002911882 · LRFN4/SALM3 phylogenetic node SUPPORTS TRANSFER |
| GO:1905606 regulation of presynapse assembly | IBA GO_REF:0000033 | MODIFY | Summary: SALM3 induces excitatory and inhibitory presynaptic differentiation in contacting axons, so the inferred regulatory process is correct but is more precisely positive. Reason: The exact Lrfn4/SALM3 donor traces to direct gene-specific evidence from PMID:20410109. GO:1905608 captures SALM3's positive effect on presynapse assembly and distinguishes it from the negative cis-regulatory role of SALM4/LRFN3. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:2385612 · mouse Lrfn4/SALM3 SUPPORTS TRANSFER The donor evidence demonstrates induction, not inhibition, of presynaptic differentiation. PANTHER:PTN002911882 · LRFN4/SALM3 phylogenetic node SUPPORTS TRANSFER Proposed replacements: positive regulation of presynapse assembly |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location vocabulary mapping assigns the broad membrane term to LRFN4. Reason: Human LRFN4 has a cleaved signal peptide and a single transmembrane helix, and its more specific cell-surface and synaptic membrane locations are independently supported. The broad location is correct. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0162 · membrane controlled vocabulary SUPPORTS TRANSFER |
| 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-interactome screen reported LRFN4 binding to NOTCH2NLA, but the generic term does not identify a biological molecular function. Reason: The exact WITH/FROM partner is Q7Z3S9 (NOTCH2NLA). This single high-throughput interaction has no focused validation or established role in LRFN4's synaptic adhesion mechanism, so it should not be treated as a core function or generalized to an informative binding activity. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: The HuRI screen reported eight binary partners for LRFN4, but the generic protein-binding term and the heterogeneous partner set do not define a coherent molecular function. Reason: The ordered WITH/FROM set comprises CYSRT1, P4HB, NOTCH2NLC, four keratin-associated proteins, and ADAMTSL4. These high-throughput calls lack LRFN4-focused physiological validation and are unrelated to its established SALM3-LAR-RPTP synaptic adhesion mechanism; retain them as interaction data, not as core GO function. Supporting Evidence: PMID:32296183 the cellular function of most individual PPIs remains to be elucidated. |
| GO:0005515 protein binding | IPI PMID:32822567 A Human IgSF Cell-Surface Interactome Reveals a Complex Netw... | MODIFY | Summary: The human cell-surface interactome study supports LRFN4/SALM3 binding to PTPRF, PTPRD, and PTPRS, but generic protein binding obscures the cell-adhesion-molecule context. Reason: The exact WITH/FROM accessions encode the three LAR-family receptor phosphatases. Their extracellular binding to SALM3 is experimentally supported and is central to transsynaptic adhesion; GO:0050839 captures this more informatively than GO:0005515 without asserting homophilic adhesion or transferring roles from another SALM paralog. Proposed replacements: cell adhesion molecule binding Supporting Evidence: PMID:32822567 With the exception of PTPRF-SALM4, we observed binding of all LAR-PTPRs to all SALMs |
| GO:0009986 cell surface | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfers cell-surface localization from mouse Lrfn4/SALM3 to human LRFN4. Reason: Q80XU8 and ENSMUSP00000050039 represent the exact mouse Lrfn4 ortholog, whose record carries direct cell-surface evidence. Conserved type-I membrane topology independently supports the transfer. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q80XU8 · mouse Lrfn4/SALM3 SUPPORTS TRANSFER ensembl:ENSMUSP00000050039 · mouse Lrfn4 protein SUPPORTS TRANSFER |
| GO:0098839 postsynaptic density membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfers postsynaptic-density-membrane localization from the exact rat Lrfn4/SALM3 ortholog. Reason: D4ABX8 and ENSRNOP00000026169 are rat Lrfn4, whose current record has direct SALM3 localization evidence from PMID:20410109. This gene-specific transfer is secure. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:D4ABX8 · rat Lrfn4/SALM3 SUPPORTS TRANSFER ensembl:ENSRNOP00000026169 · rat Lrfn4 protein SUPPORTS TRANSFER |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfers glutamatergic-synapse localization from mouse Lrfn4/SALM3. Reason: The donor is the exact ortholog, and gene-specific rodent experiments place SALM3 in synaptic fractions and show excitatory presynaptic induction. This does not imply SALM1/SALM2 glutamate-receptor-binding activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q80XU8 · mouse Lrfn4/SALM3 SUPPORTS TRANSFER ensembl:ENSMUSP00000050039 · mouse Lrfn4 protein SUPPORTS TRANSFER |
| GO:0098982 GABA-ergic synapse | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfers GABA-ergic-synapse localization from mouse Lrfn4/SALM3. Reason: The exact rodent Lrfn4 evidence shows SALM3-driven inhibitory as well as excitatory presynaptic differentiation. The localization therefore reflects a gene-specific SALM3 property rather than family-wide transfer. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q80XU8 · mouse Lrfn4/SALM3 SUPPORTS TRANSFER ensembl:ENSMUSP00000050039 · mouse Lrfn4 protein SUPPORTS TRANSFER |
| GO:0099151 regulation of postsynaptic density assembly | IEA GO_REF:0000107 | MODIFY | Summary: SALM3 promotes PSD-95 clustering, so the exact-ortholog transfer is biologically sound but the unsigned regulatory term is less precise than the evidence permits. Reason: Q80XU8 is mouse Lrfn4/SALM3, and its donor annotation traces to direct SALM3 evidence from PMID:20410109. GO:0160036 captures the positive direction while avoiding any transfer of SALM1/SALM2 receptor-organizing functions. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q80XU8 · mouse Lrfn4/SALM3 SUPPORTS TRANSFER The gene-specific donor evidence shows increased PSD-95 clustering. ensembl:ENSMUSP00000050039 · mouse Lrfn4 protein SUPPORTS TRANSFER Proposed replacements: positive regulation of postsynaptic density assembly |
| GO:0099560 synaptic membrane adhesion | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfers synaptic membrane adhesion from mouse Lrfn4/SALM3 to the human ortholog. Reason: The donor is exact and gene-specific evidence supports SALM3 binding to presynaptic LAR-family receptor phosphatases. This is a core LRFN4 transsynaptic role, distinct from SALM4 cis inhibition. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q80XU8 · mouse Lrfn4/SALM3 SUPPORTS TRANSFER ensembl:ENSMUSP00000050039 · mouse Lrfn4 protein SUPPORTS TRANSFER |
| GO:1905606 regulation of presynapse assembly | IEA GO_REF:0000107 | MODIFY | Summary: SALM3 induces presynaptic differentiation, so the exact-ortholog transfer is correct but should record the positive regulatory direction. Reason: The mouse Lrfn4 donor traces to direct SALM3 induction experiments. GO:1905608 is the precise term for this positive role and avoids conflating LRFN4 with the inhibitory SALM4/LRFN3 mechanism. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q80XU8 · mouse Lrfn4/SALM3 SUPPORTS TRANSFER The gene-specific evidence shows induction of presynaptic differentiation. ensembl:ENSMUSP00000050039 · mouse Lrfn4 protein SUPPORTS TRANSFER Proposed replacements: positive regulation of presynapse assembly |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8849891 | ACCEPT | Summary: Reactome places human SALM3/LRFN4 in membrane-associated complexes with PSD-95-family scaffolds. Reason: SALM3 is explicitly included among SALMs1-3 that bind DLG-family PDZ scaffolds and are enriched in synaptic fractions. Together with its type-I topology, this supports the broad plasma-membrane location. Supporting Evidence: Reactome:R-HSA-8849891 SALMs 1-3 interact with the PDZ domain containing proteins PSD 95 (DLG4) and synapse associated protein 97 (SAP97 or DLG1) and SAP102 (DLG3) |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8849900 | ACCEPT | Summary: Reactome models SALM3/LRFN4 in cis homo- and heteromeric complexes with SALM1 and SALM2 at the membrane. Reason: SALM3 is directly included in the cis complexes, and its single-pass surface topology independently supports plasma-membrane localization. Cis association is not interpreted as trans homophilic adhesion. Supporting Evidence: Reactome:R-HSA-8849900 SALM1, SALM2, and SALM3 form homo- and heteromeric complexes in a cis manner. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8855648 | ACCEPT | Summary: Reactome places SALM3/LRFN4 in a transsynaptic complex with LAR-family receptor protein tyrosine phosphatases. Reason: The event is explicitly SALM3-specific and agrees with human ectodomain binding evidence and LRFN4's type-I membrane topology. The broad plasma-membrane location is therefore sound. Supporting Evidence: Reactome:R-HSA-8855648 SALM3 interacts with LAR family receptor protein tyrosine phosphatases (LAR-RPTPs) in a transynaptic manner that is dependent upon a splice insert in LAR-RPTPs. |
| GO:0050900 leukocyte migration | IMP PMID:21704618 A neuronal transmembrane protein LRFN4 induces monocyte/macr... | NEW | Summary: Human LRFN4 regulates transendothelial migration of monocytic cells and contributes to monocyte/macrophage migration. Reason: This is direct human THP-1 and primary-monocyte evidence for a non-neuronal LRFN4 process that is absent from the current annotation set. The leukocyte-migration term captures the demonstrated cell movement without assuming an unidentified extracellular ligand or receptor activity. Supporting Evidence: PMID:21704618 Furthermore, we demonstrated that LRFN4 signaling regulated both the transendothelial migration of THP-1 cells and the elongation of THP-1 cells via actin cytoskeleton reorganization. |
| GO:0030165 PDZ domain binding | IPI PMID:16630835 SALM synaptic cell adhesion-like molecules regulate the diff... | NEW | Summary: Human LRFN4/SALM3 interacts with the PDZ-scaffold proteins DLG1, DLG2, DLG3 and DLG4; deletion of its terminal residues 633-635 abolishes DLG1, DLG3 and DLG4 binding. Reason: PMID:16630835 is direct human interaction evidence curated on the LRFN4 UniProtKB record. DLG1, DLG2, DLG3 and DLG4 are human PDZ-scaffold interaction partners, and loss of the final three residues demonstrates that the C-terminal PDZ-binding tail is necessary for DLG1/3/4 binding. IPI therefore replaces the prior ISO transfer from rat Lrfn4; the rat study remains bounded corroboration for neuronal PSD-95 association. Supporting Evidence: PMID:16630835 cell adhesion-like molecules termed SALM that interacts with the abundant postsynaptic density (PSD) protein PSD-95. file:human/LRFN4/LRFN4-uniprot.txt Interacts with DLG1, DLG2, DLG3 and DLG4. file:human/LRFN4/LRFN4-uniprot.txt Missing: Loss of DLG1-, DLG3- and DLG4-binding. PMID:20410109 SALM1, SALM2, and SALM3 interact with postsynaptic density-95 (PSD-95) in vitro via their PDZ-binding C termini |
| GO:0032956 regulation of actin cytoskeleton organization | IMP PMID:21704618 A neuronal transmembrane protein LRFN4 induces monocyte/macr... | NEW | Summary: LRFN4 signaling regulates monocytic-cell migration and elongation through actin-cytoskeleton reorganization. Reason: Direct human-cell perturbation links LRFN4 to actin reorganization, and a follow-up study places 14-3-3, NCK1 and Rac1 in this pathway. The regulatory process is supported, whereas a specific intrinsic signaling molecular function remains unresolved. Supporting Evidence: PMID:21704618 Furthermore, we demonstrated that LRFN4 signaling regulated both the transendothelial migration of THP-1 cells and the elongation of THP-1 cells via actin cytoskeleton reorganization. PMID:22677168 Finally, we demonstrated that a Rac1 small GTPase was involved in LRFN4-mediated cell elongation. |
Loading supporting content…
Download this section (compressed HTML)Q: Which human LAR-RPTP splice isoforms engage endogenous postsynaptic LRFN4, and which receptor is required for excitatory versus inhibitory presynapse assembly?
Q: How do the LRFN4 extracellular dimerization/receptor-binding interfaces and the cytoplasmic ESVV-PDZ interaction cooperate across the postsynaptic membrane?
Q: Which of DLG1, DLG2, DLG3, DLG4 and other PDZ scaffolds occupy endogenous LRFN4 in human neurons, and how does tail-dependent binding control postsynaptic-density assembly and neurite growth?
Q: What activates LRFN4 in human monocytes, and how are 14-3-3, NCK1 and Rac1 ordered between LRFN4 engagement, actin remodeling and transendothelial migration?
Q: Do LRFN4-containing cis SALM homo- or heteromers control surface delivery, LAR-RPTP avidity or synaptic signaling without mediating SALM-SALM trans adhesion?
Experiment: Generate LRFN4-null human induced-pluripotent-stem-cell-derived neurons and rescue them with endogenous-level wild-type LRFN4 or structure-guided LRR-Ig interface mutants. Perturb PTPRF, PTPRD and PTPRS singly and combinatorially in the apposed presynaptic cells, control their mini-exon content, and quantify trans-synaptic proximity, excitatory and inhibitory presynaptic marker recruitment, synapse density and miniature synaptic currents.
Hypothesis: Endogenous human neuronal LRFN4 promotes presynapse assembly through a splice-selective trans interaction with LAR-family receptor phosphatases.
Type: Direction- and splice-resolved human-neuron epistasis
Experiment: Introduce an endogenous ESVV deletion in human neurons and compare wild-type, motif-deleted and repaired cells by quantitative LRFN4 interactomics, proximity labeling, PSD nanostructure imaging, scaffold and receptor mobility measurements, neurite morphology and electrophysiological rescue.
Hypothesis: The human LRFN4 ESVV motif recruits a defined PDZ-scaffold ensemble that couples trans-synaptic adhesion to postsynaptic-density assembly.
Type: Endogenous PDZ-tail structure-function analysis
Experiment: Purify glycosylated full-length human proteins, reconstitute them in nanodiscs or apposed supported membranes, determine stoichiometry and conformational ensembles by cryo-electron microscopy and cross-linking mass spectrometry, and test structure-guided interface mutants in matched neuron cocultures.
Hypothesis: Full-length LRFN4 and a mini-exon-containing LAR-RPTP form a flexible membrane- spanning 2:2 adhesion assembly whose dimer and receptor interfaces are both required for signaling.
Type: Full-length membrane-complex structural analysis
Experiment: Endogenously tag LRFN4 in primary human monocytes and differentiated macrophages, use extracellular cross-linking and cytoplasmic proximity labeling across migration stimuli to identify upstream ligands and signaling partners, then test their order with acute perturbations, domain-specific rescue, live Rac1 biosensors, actin imaging and transendothelial-migration assays.
Hypothesis: A stimulus-dependent extracellular interaction activates a distinct LRFN4- 14-3-3-NCK1-Rac1 pathway that drives human monocyte migration.
Type: Human monocyte ligand discovery and signaling epistasis
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The endogenous human-neuronal requirement for each SALM3-LAR-RPTP pair, the presynaptic splice isoforms that engage LRFN4, and the relative contribution of PTPRF, PTPRD and PTPRS to excitatory versus inhibitory presynapse assembly are unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human ectodomains bind all three LAR-family receptors, and rodent experiments show mini-exon-dependent trans-synaptic binding and strong loss of SALM3-induced presynaptic differentiation after triple receptor knockdown. These findings do not resolve partner-specific occupancy or necessity in human neurons.
Significance: Partner- and splice-specific resolution is needed to connect the conserved human binding activity to physiological synapse organization and to avoid treating all ectodomain interactions as functionally equivalent.
What would resolve it: Use paired human excitatory and inhibitory neurons with compartment-specific endogenous tagging and single, combined and splice-selective LAR-RPTP perturbation, followed by interface-mutant rescue, proximity measurements, synaptic imaging and electrophysiology.
Provenance (the field's own admissions):
Gap: The architecture and conformational dynamics of full-length human LRFN4 alone and in a membrane-spanning LRFN4-LAR-RPTP adhesion complex have not been determined.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Mouse SALM3 LRR fragments form stable antiparallel dimers, and SAXS supports a flexible 2:2 assembly of partial SALM3 and PTPσ ectodomains. The crystallized material is not full-length human LRFN4, and the low-resolution complex model is an ensemble average rather than a single rigid conformation.
Significance: A full-length membrane-context structure would define how dimerization, splice- dependent receptor engagement and intracellular scaffold coupling are coordinated.
What would resolve it: Reconstitute glycosylated full-length human LRFN4 with defined human LAR-RPTP splice isoforms in nanodiscs or apposed membranes and combine cryo-electron microscopy, cross-linking mass spectrometry and structure-guided functional rescue.
Provenance (the field's own admissions):
Gap: Which of the demonstrated DLG1, DLG2, DLG3 and DLG4 partners, or other PDZ proteins, occupy endogenous LRFN4 in human neurons, and how that interaction module coordinates postsynaptic-density assembly with extracellular LAR-RPTP adhesion, remain unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human LRFN4 binds DLG1, DLG2, DLG3 and DLG4, and deleting residues 633-635 eliminates DLG1/3/4 binding, while rodent SALM3 recruits PSD-95 when artificially clustered on dendrites. These results establish tail-dependent binding but do not establish endogenous human-neuronal partner stoichiometry, the deletion effect on DLG2, or coupling to the trans-synaptic complex.
Significance: This cytoplasmic linkage is the likely route from surface adhesion to postsynaptic organization, but its human molecular composition and causal hierarchy are not known.
What would resolve it: Compare endogenous wild-type and ESVV-deleted LRFN4 in human neurons using quantitative tail interactomics, proximity labeling, super-resolution imaging, receptor-mobility measurements and matched functional rescue.
Provenance (the field's own admissions):
Gap: The extracellular ligand or activating condition for LRFN4 signaling in human monocytes and the mechanism linking its cytoplasmic region to 14-3-3, NCK1 and Rac1 are not established.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Direct human-cell studies show that LRFN4 regulates transendothelial migration and elongation through actin reorganization and that 14-3-3, NCK1 and Rac1 participate in this pathway. They do not identify the initiating extracellular interaction or establish whether neuronal and monocytic LRFN4 use the same intracellular logic.
Significance: Defining the upstream trigger and signaling topology is necessary to understand when LRFN4 controls innate-immune-cell movement and whether this role intersects with its adhesion activity.
What would resolve it: Endogenously tag LRFN4 in primary human monocytes, identify stimulus-dependent extracellular and cytoplasmic partners by cross-linking and proximity proteomics, and test candidates with acute perturbation, domain-specific rescue, Rac1 activity imaging and transendothelial-migration assays.
Provenance (the field's own admissions):
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)