| 2007 |
Necl4 (CADM4) is expressed by myelinating Schwann cells along the internodes and serves as the glial binding partner for axonal Necl1 (CADM3); the heterophilic trans-interaction between Necl4 and Necl1 mediates Schwann cell adhesion to axons. Disruption of this interaction using soluble extracellular domains or expression of dominant-negative Necl4 in Schwann cells inhibits peripheral nervous system myelination. |
Soluble extracellular domain competition assay, dominant-negative overexpression in Schwann cells, co-culture myelination assay, immunofluorescence localization |
Nature neuroscience |
High |
17558405
|
| 2013 |
Genetic deletion of Cadm4 specifically in Schwann cells (DHH-Cre/Cadm4(fl/fl)) or expression of a dominant-negative Cadm4 lacking its cytoplasmic domain (Tg(mbp-Cadm4dCT)) causes focal hypermyelination (tomacula and myelin outfoldings), abnormal axon-glial contact, redistribution of ion channels along the axon, impaired motor function, and slower nerve conduction velocity; Cadm4's cytoplasmic domain is required for normal myelin unit growth and axonal membrane organization in the PNS. |
Conditional knockout (Cre/lox), dominant-negative transgenic mice, electron microscopy, immunostaining of ion channels, nerve conduction velocity measurements, behavioral assays |
The Journal of neuroscience |
High |
23825401
|
| 2001 |
TSLL2 (CADM4) encodes a transmembrane immunoglobulin superfamily protein; its expression is lost or markedly reduced in human glioma cell lines and some prostate cancer cell lines, and its cytoplasmic domain shows structural homology to the tumor suppressor TSLC1, suggesting functional relevance of this domain. |
cDNA cloning, structural homology analysis, expression analysis in cancer cell lines |
Oncogene |
Low |
11536053
|
| 2006 |
TSLL2/CADM4 protein localizes to lateral membranes in polarized MDCK cells, forms homodimers, and induces Ca2+/Mg2+-independent cell aggregation upon overexpression, indicating homophilic trans-interaction. Introduction of TSLL2 into a prostate cancer cell line (PPC-1) strongly suppresses subcutaneous tumor formation in nude mice. |
Confocal microscopy of polarized cells, cell aggregation assay, homodimerization (pulldown/co-IP), xenograft tumor suppression assay |
Oncogene |
Medium |
16261159
|
| 2011 |
CADM4 associates in cis with the actin-binding protein 4.1B (but not 4.1N) in normal human kidney proximal tubule lysates, as shown by immunoprecipitation. Introduction of CADM4 into a renal cell carcinoma line (786-O) suppresses tumor formation in nude mice, supporting a tumor suppressor function. |
Immunoprecipitation/Western blotting from human kidney lysates, xenograft tumor suppression assay |
International journal of cancer |
Medium |
21544807
|
| 2013 |
Necl-4/CADM4 interacts in cis with ErbB3 through their extracellular regions, recruits PTPN13, and inhibits heregulin-induced activation of ErbB2/ErbB3 signaling. Additionally, Necl-4 interacts in cis with integrin α6β4 through extracellular regions and inhibits phorbol ester-induced disassembly of hemidesmosomes. |
Co-immunoprecipitation, pulldown assay, phosphorylation assays for ErbB2/ErbB3 downstream signaling, hemidesmosome disassembly assay |
Genes to cells |
Medium |
23611113
|
| 2013 |
In the CNS, genetic knockout of Necl-4/Cadm4 does not affect oligodendrocyte differentiation, myelin formation, or PNS myelination in developing mice, indicating that Cadm4 is dispensable for CNS and PNS axonal myelination under these conditions. |
Necl4 knockout mouse generation, immunostaining of myelin markers, electron microscopy of PNS and CNS myelin |
PloS one |
Medium |
23700466
|
| 2014 |
In zebrafish, cadm4 knockdown dramatically expands the cardiac outflow tract (OFT) while overexpression greatly diminishes it; cadm4 limits the production of OFT progenitor cells and the duration of their accumulation at the arterial pole, placing Cadm4 as a regulator of second heart field deployment. |
Morpholino knockdown, mRNA overexpression, cardiac progenitor cell quantification, live imaging in zebrafish |
Cell reports |
Medium |
24813897
|
| 2015 |
In confluent vascular endothelial cells, Necl-4/CADM4 is upregulated and localizes at cell-cell contact sites where it cis-interacts with VEGFR2, recruiting PTPN13 to inhibit VEGFR2 tyrosine phosphorylation and reduce cell movement and proliferation. In sparse cells, Necl-4 accumulates at leading edges where it inhibits ROCK via PTPN13, facilitating VEGF-induced Rac1 activation and ERK1/2 activation to enhance movement and proliferation. |
Co-immunoprecipitation (Necl-4 with VEGFR2), knockdown experiments, VEGFR2 phosphorylation assays, Rac1 and ROCK activity assays, cell migration and proliferation assays |
PloS one |
Medium |
25893857
|
| 2017 |
Necl-4/CADM4 enhances VEGF-induced activation of the PLCγ-c-Raf-MEK-ERK signaling pathway in endothelial cells without affecting VEGFR2 phosphorylation or internalization; this effect is independent of PTPN13 or ROCK. |
siRNA knockdown of Necl-4, phosphorylation assays for PLCγ, c-Raf, MEK, ERK and VEGFR2, VEGFR2 internalization assay |
Biochemical and biophysical research communications |
Medium |
28601637
|
| 2018 |
Cadm4/Necl-4 expressed by oligodendrocytes promotes formation of axoglial contact sites, but excessive adhesion via a membrane-bound extracellular domain (Cadm4dCT) prevents myelin elongation. Transgenic mice expressing Cadm4dCT in oligodendrocytes are hypomyelinated and show myelination of neuronal somata; these abnormalities require specific neuron-glial interaction and depend on axonal Cadm receptors (Cadm3/Necl-1 and Cadm2/Necl-3). |
Transgenic mouse overexpression, cultured oligodendrocyte-neuron co-culture, nanofiber culture, knockout of axonal Cadm receptors, electron microscopy, immunostaining |
Neuron |
High |
30551998
|
| 2018 |
The cytoplasmic terminal region (CTR) of Necl-4/Cadm4 contains a PDZ-binding motif that directly binds the first PDZ domain of Par-3. Necl-4 and Par-3 colocalize along the inner (adaxonal) Schwann cell membrane and co-precipitate from Schwann cell lysates. Knockdown of Necl-4 perturbs Par-3 localization to the inner Schwann cell membrane in myelinating co-cultures, implicating Necl-1/Necl-4 interaction in recruiting Par-3 to establish Schwann cell radial polarity. |
Unbiased proteomic PDZ-domain screen with Necl-4 CTR, co-immunoprecipitation from Schwann cell lysates, immunofluorescence colocalization, siRNA knockdown in myelinating co-cultures |
Glia |
High |
30585357
|
| 2022 |
Cadm4 forms a complex with Mpp6 (Pals2), protein band 4.1G (Epb41l2), and Lin7 in Schmidt-Lanterman incisures (SLIs) of peripheral nerve myelin, as identified by mass spectrometry-based proteomics of purified myelin. This complex is increased in aged FA2H-deficient mouse sciatic nerves alongside increased SLI frequency. |
Mass spectrometry-based proteomics of purified myelin, quantitative protein analysis, SLI counting by electron/light microscopy |
Molecular neurobiology |
Medium |
35445918
|
| 2024 |
Cadm4 undergoes palmitoylation at cysteine-347 (C347), catalyzed by ZDHHC3, which is required for stable Cadm4 localization at the plasma membrane. Mutation C347A blocks palmitoylation, causes Cadm4 internalization and degradation. Cadm4-KI (C347A knock-in) mice show severe CNS myelin abnormalities (loss, demyelination, hypermyelination), impaired neuronal transmission, and cognitive deficits. Genetic deletion of ZDHHC3 reduces Cadm4 palmitoylation and causes CNS myelination defects phenocopying Cadm4-KI. Cadm4 may regulate oligodendrocyte differentiation via the WNT-β-Catenin pathway. |
Site-directed mutagenesis (C347A), palmitoylation assay, knock-in mouse model, ZDHHC3 knockout mice, plasma membrane fractionation, electron microscopy, electrophysiology, behavioral assays |
Signal transduction and targeted therapy |
High |
39327467
|
| 2025 |
Necl-4/CADM4 is expressed in GABAergic inhibitory neurons and localizes at GABAergic synapses on inhibitory neurons in the hippocampus. Genetic ablation of Necl-4 increases GABAergic synapse density on inhibitory neurons and enhances GABAergic synaptic currents, effects mediated through ErbB4 activation. This leads to high-frequency firing, excitotoxicity-mediated neuronal death, and hippocampal neuronal loss with synaptic degeneration. |
Necl-4 KO mouse, immunofluorescence of hippocampal neurons and cultured neurons, electrophysiology (mIPSC recording), ErbB4 activation assays, cell death assays |
Molecular neurobiology |
Medium |
40728771
|