UniProtKB reviewed entry for human LRFN4 (Q6PJG9)
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Human LRFN4 interacts with the PDZ-scaffold proteins DLG1, DLG2, DLG3 and DLG4.
"Interacts with DLG1, DLG2, DLG3 and DLG4."
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Deletion of LRFN4 residues 633-635 causes loss of DLG1, DLG3 and DLG4 binding; the record does not report the effect on DLG2 binding.
"Missing: Loss of DLG1-, DLG3- and DLG4-binding."
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
A proteome-scale map of the human interactome network.
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The source is a proteome-scale human binary-interaction map rather than an LRFN4-focused mechanistic study.
"Here, we describe a systematic map of ?14,000 high-quality human"
A reference map of the human binary protein interactome.
A Human IgSF Cell-Surface Interactome Reveals a Complex Network of Protein-Protein Interactions.
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Human SALM3 ectodomain binds each of the three LAR-family receptor phosphatases in the study's SPR survey.
"With the exception of PTPRF-SALM4, we observed binding of all LAR-PTPRs to all SALMs"
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The SALM-LAR-RPTP pairs displayed differing maximal SPR responses, consistent with a range of affinities rather than equivalent interactions.
"PTPR-SALM pairs exhibited differences in maximum response units (RU), a relative comparison of binding strength, suggesting a spectrum of binding affinities may exist among LAR-PTPRs and SALMs"
SALM synaptic cell adhesion-like molecules regulate the differentiation of excitatory synapses.
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The paper identifies SALMs as a family that interacts with the postsynaptic PDZ scaffold PSD-95.
"cell adhesion-like molecules termed SALM that interacts with the abundant
postsynaptic density (PSD) protein PSD-95."
The SALM family of adhesion-like molecules forms heteromeric and homomeric complexes.
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In rat brain, SALMs 1-3, including SALM3/LRFN4, strongly associate with one another in cis complexes.
"In brain, we found
that SALMs 1-3 strongly co-immunoprecipitated with each other, whereas SALMs 4
and 5 did not, suggesting that SALMs 4 and 5 mainly form homomeric complexes."
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SALMs 1-3 did not form the homophilic trans-cellular associations observed for SALM4 and SALM5.
"Both SALMs 4 and 5 formed homophilic, but not heterophilic associations,
whereas no trans associations were formed by the other SALMs."
Synaptic adhesion-like molecules (SALMs) promote neurite outgrowth.
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Overexpression of every SALM family member, including SALM3, enhanced neurite outgrowth in cultured hippocampal neurons, with paralog-dependent phenotypes.
"Over-expression of each SALM resulted in enhanced
neurite outgrowth, but with different phenotypes."
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The PDZ-binding tails shared by SALMs 1-3 are required for most measured neurite-outgrowth effects.
"Through over-expression of deletion constructs, we found
that the C-terminal PDZ binding domains of SALMs 1-3 are required for most
aspects of neurite outgrowth."
Reticulon 3 is an interacting partner of the SALM family of adhesion molecules.
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Reticulon 3C co-immunoprecipitated with SALMs 1-4 from brain, providing family-level evidence for a possible trafficking interaction that includes SALM3.
"A 19-kDa band, identified as reticulon 3C, bound to all
four SALMs, whereas a 90-kDa band, which did not comigrate with any known
reticulon 3 variant, bound to SALMs 2 and 3."
Selected SALM (synaptic adhesion-like molecule) family proteins regulate synapse formation.
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SALM3 expression induces excitatory and inhibitory presynaptic differentiation in contacting axons.
"We found that expression of the SALM family proteins SALM3 and SALM5 in nonneural and neural cells induces both excitatory and inhibitory presynaptic differentiation in contacting axons."
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SALM3 is enriched in synaptic fractions and forms a strong complex with the postsynaptic scaffold PSD-95.
"SALM3 and SALM5 proteins are enriched in synaptic fractions, and form strong (SALM3) or weak (SALM5) complexes with postsynaptic density-95 (PSD-95), an abundant postsynaptic scaffolding protein at excitatory synapses."
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Artificial aggregation of SALM3 on dendritic surfaces induces PSD-95 clustering.
"Aggregation of SALM3, but not SALM5, on dendritic surfaces induces clustering of PSD-95."
A neuronal transmembrane protein LRFN4 induces monocyte/macrophage migration via actin cytoskeleton reorganization.
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Human LRFN4 expression increases in THP-1 cells and primary monocytes during macrophage differentiation.
"We also found that expression of LRFN4 in the monocytic cell line THP-1
and in primary monocytes was upregulated following macrophage differentiation."
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LRFN4 signaling regulates THP-1 transendothelial migration and cell elongation through actin-cytoskeleton reorganization.
"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."
A neuronal transmembrane protein LRFN4 complexes with 14-3-3s and NCK1 to induce morphological change in monocytic cells via Rac1-mediated actin cytoskeleton reorganization.
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14-3-3 and NCK proteins complex with LRFN4 and contribute to LRFN4-mediated elongation of monocytic cells.
"We found that 14-3-3 and
NCK proteins complexed with LRFN4, and they were involved in LRFN4-mediated cell
elongation."
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Rac1 is required in the pathway producing LRFN4-mediated monocytic-cell elongation.
"Finally, we demonstrated that a Rac1 small GTPase was involved in
LRFN4-mediated cell elongation."
Splicing-Dependent Trans-synaptic SALM3-LAR-RPTP Interactions Regulate Excitatory Synapse Development and Locomotion.
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Postsynaptic SALM3 binds all three presynaptic LAR-RPTPs in an alternative-splicing-dependent trans-synaptic interaction.
"In the present study, we demonstrated that SALM3 trans-synaptically interacts with all three types of presynaptic LAR-RPTPs in an alternative splicing-dependent manner."
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Combined depletion of the three LAR-RPTPs strongly suppresses SALM3-induced presynaptic differentiation.
"In triple knockdown of LAR-RPTPs, SALM3-induced synapsin I clustering was decreased by 85.2% ± 3.0%, suggesting that LAR-RPTPs play a major role in SALM3-dependent presynaptic differentiation."
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Mouse Salm3 loss reduces excitatory-synapse density and mEPSC frequency in hippocampal CA1, with sparse postsynaptic rescue supporting a cell-autonomous role.
"The Salm3−/− mice data indicate that SALM3 is important for excitatory synapse development in the hippocampal CA1 region, as supported by substantial reductions in mEPSC frequency (~52.3%) and PSD density (~14.5%)."
SALM/Lrfn Family Synaptic Adhesion Molecules.
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The review explicitly maps SALM3 to Lrfn4 and distinguishes it from SALM4/Lrfn3.
"A total of five members of the SALM family have been identified: SALM1/Lrfn2, SALM2/Lrfn1, SALM3/Lrfn4, SALM4/Lrfn3 and SALM5/Lrfn5"
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SALM3 and SALM5 have synaptogenic activity and interact trans-synaptically with presynaptic LAR-RPTPs.
"SALM3 and SALM5, which unlike other SALMs possess synaptogenic activities (Mah et al., 2010), have been found to interact trans-synaptically with presynaptic LAR family receptor tyrosine phosphatases"
Structural basis of SALM3 dimerization and synaptic adhesion complex formation with PTPσ.
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The isolated mouse SALM3 LRR domain forms a stable antiparallel dimer, with the LRR fragment alone sufficient for dimerization in solution.
"Thus, these measurements verified that the LRR domain is sufficient alone for stable dimer formation."
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SAXS supports a flexible 2:2 assembly between partial SALM3 and PTPσ extracellular-domain constructs rather than a single rigid full-length complex conformation.
"It should be noted that while it is possible to obtain a good fit to the model with P2 symmetry constraint, we stress that due to the limited resolution of SAXS data, the model is likely representing an average snapshot of a number of conformations present in solution."
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Mutations disrupting the modeled SALM3-PTPσ interfaces or the SALM3 LRR dimer suppress presynaptic differentiation in a heterologous neuron coculture assay.
"The synaptogenic activity of SALM3 was clearly detected with the WT SALM3, but the interface mutants targeting the SALM3-PTPσ interaction abolished synapsin I clustering"
SALMs 1-3 bind to PSD-95 family members
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Reactome models SALM3 with PSD-95-family PDZ scaffolds at the plasma membrane.
"SALMs 1-3 interact with the PDZ domain containing proteins PSD 95 (DLG4) and synapse associated protein 97 (SAP97 or DLG1) and SAP102 (DLG3)"
SALMs1-3 bind each other in cis interactions
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Reactome models SALM1, SALM2 and SALM3 in homo- and heteromeric cis complexes.
"SALM1, SALM2, and SALM3 form homo- and heteromeric complexes in a cis manner."
SALM3 binds LAR-RPTP
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Reactome models splice-dependent trans-synaptic binding of SALM3 to LAR-family receptor phosphatases.
"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."