Nectin-3, also known asnectin cell adhesion molecule 3, is aprotein that in humans is encoded by theNECTIN3gene.
Nectin-3 belongs to the family of immunoglobulin(Ig)-like cellular adhesion molecules involved inCa2+-independent cellular adhesion[5] in several tissues during the development[6] and was firstly isolated at the turn of 20th and 21st century.[7]
Nectin-3 has threesplicing variants, nectin-3α, which is the biggest one, nectin-3β and the smallest variant nectin-3γ.
Nectin-3α (same as the other splicing variants) is abundately expressed intestis, on slightly lower level it is also expressed inheart,brain,liver orkidney. It has been also proved that nectin-3α is together withnectin-2 localize at thejunctional complex regions insmall intestina absorptive epithelia. Nectin-3γ is also detectable inlung, liver and kidney.[7] Nectin-3 is expressed not only onepithelial cells as another nectins, but there was shown that, as the only member of nectin family, it is expressed also onT- lymphocytes.[8]
The structural properties of nectin-3α is similar tonectin-1, it has three Ig-like domains at the extracellular region and theC-terminal conserved motif at the cytoplasmic region. Thehomology of aa (amino aci)) of extracellular domains between Nectin-1 and Nectin-3α is 35,9%. Another splicing variants vary in the number of aa, molecular weight and the structural properties. All of them have the identical extracellular region. Nectin-3β and nectin-3γ have the same transmembrane and cytoplasmic regions, which vary from nectin-3α. Nectin-3γ lack of C-terminal domain.[7] With the intracellular domain nectins bind their assosicated adaptor protein afadin[9] which plays role in the formation of variety of cell-cell junctions.[10] Nectin-3γ in not able to bind afadin due to lacking C-terminal domain.[7]
All nectins are able to formcis-homo dimer interactions, which simply means they can create dimer of two alike molecules on the same cell membrane. Further, nectin-3α can also interact with Nectin-1/2α in so calledtrans-hetero interaction.[7]
Nectin-3 is expressed bygranule cells indentate gyrus and the expression levels are developmentally regulated and reduced by early postnatal stress. On mice model, it has been shown that the early-life stress impaires the long-termspatial memory andtemporal order memory. It is also very probable that the nectin-3 in dentate gyrus neurons modulate adultneurogenesis and dendritic spine plasticity.[11] It has been proven that combination nectin-3/nectin-1 is very important in formation ofsynapses in brain,hippocampus and that the formation of hetero-trans-dimers between nectin-1 and nectin-3 determines the position and size of the synapses,in vitro.[12]In vivo, it has been shown that the function of nectin-3 is crutial during the critical periods of thevisual cortex development and that it is important not only for synapses formation but also for the synaptic refinement. Also it has been proven that there is a high importance of nectin-3 for the dendritic spine densities (which simply represent the sites of synaptic contacts) on visual cortical neurons.[13] The nectin-1/nectin-3 trans-interaction has been shown to be very important to establishing theadhesion between the pigment and non-pigment cell layers of theciliary epithelia, which is essential for themorphogenesis of theciliary body of the eye.[14]
Nectin-3 is important role player inspermatid development. The nectin-3–/– male mice were found to have defects in the later steps of spermmorphogenesis, exhibiting distortednuclei and abnormal distribution ofmitochondria. The loss of nectin-3 in male mice leads to male-specificinfertility.[15] It has been shown that thechronic stress negatively influences the amount of nectin-3 in the testis and also the malespermatogenesis function.[16]
As mentioned above, nectin-3 is the only nectin which is expressed on T- lymphocytes. The interaction between nectin-3 on T-cells and other nectins onepithelial cells is very important in the lymphocytetransendothelial migration,in vitro. It has been shown that this process is dependent on nectin-2, which is expressed on epithelial cells, the blockation of nectin-2 or nectin-3 leads to inhibition of lymphocyte and alsomonocyte extravasation.[17]
Nectin-3 is highly expressed in epithelial cancer cells of humanlung adenocarcinoma. It is expressed in 80% of patients which makes it relatively strong prognostic marker. It has been shown, there are various expression patterns of nectin-3; cytoplasmic, membranous or combined. The membranous expression is connected with significantly poorer prognosis, patients with this type of expression pattern are also more likely to earlierrelapse and death.[18] Increased amounts of nectin-3 are also detectable inovaries during theovarian cancer and are correlated with poor patient prognosis. The data also suggest that the possible mechanism of nectin-3 in cellular invasion and migration is by upregulating the expression ofmatrix metalloproteinases (MMPs) MMP2 and MMP9 in ovarian cancer.[19]
Contrary to previously mentioned cancers, the amount of nectin-3 negatively correlates withPancreatic neuroendocrine tumors. The loss of this protein correlates with increased tumor progressiveness.[20]
^Takai Y, Ikeda W, Ogita H, Rikitake Y (2008-11-01). "The immunoglobulin-like cell adhesion molecule nectin and its associated protein afadin".Annual Review of Cell and Developmental Biology.24 (1):309–342.doi:10.1146/annurev.cellbio.24.110707.175339.PMID18593353.
^Hirabayashi K, Tajiri T, Bosch DE, Morimachi M, Miyaoka M, Inomoto C, et al. (February 2020). "Loss of nectin-3 expression as a marker of tumor aggressiveness in pancreatic neuroendocrine tumor".Pathology International.70 (2):84–91.doi:10.1111/pin.12881.PMID31855317.S2CID209418057.
^Reymond N, Borg JP, Lecocq E, Adelaide J, Campadelli-Fiume G, Dubreuil P, Lopez M (September 2000). "Human nectin3/PRR3: a novel member of the PVR/PRR/nectin family that interacts with afadin".Gene.255 (2):347–355.doi:10.1016/s0378-1119(00)00316-4.PMID11024295.
