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Nectin-3

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(Redirected from PVRL3)
NECTIN3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNECTIN3, CD113, CDW113, NECTIN-3, PPR3, PRR3, PVRR3, PVRL3, nectin cell adhesion molecule 3
External IDsOMIM: 607147; MGI: 1930171; HomoloGene: 9162; GeneCards: NECTIN3; OMA:NECTIN3 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

25945

58998

Ensembl

ENSG00000177707

ENSMUSG00000022656

UniProt

Q9NQS3

Q9JLB9

RefSeq (mRNA)

NM_001243286
NM_001243288
NM_015480

NM_021495
NM_021496
NM_021497

RefSeq (protein)

NP_001230215
NP_001230217
NP_056295

NP_067470
NP_067471
NP_067472

Location (UCSC)Chr 3: 111.07 – 111.28 MbChr 16: 46.21 – 46.32 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Nectin-3, also known as nectin cell adhesion molecule 3, is a protein that in humans is encoded by the NECTIN3 gene.

Nectin-3 belongs to the family of immunoglobulin(Ig)-like cellular adhesion molecules involved in Ca2+-independent cellular adhesion[5] in several tissues during the development[6] and was firstly isolated at the turn of 20th and 21st century.[7]

Structure and localization

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Nectin-3 has three splicing 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 in testis, on slightly lower level it is also expressed in heart, brain, liver or kidney. It has been also proved that nectin-3α is together with nectin-2 localize at the junctional complex regions in small intestina absorptive epitelia. Nectin-3γ is also detectable in lung, liver and kidney.[7] Nectin-3 is expressed not only on epithelial cells as another nectins, but there was shown that, as the only member of nectin family, it is expressed also on T- lymphocytes.[8]

The structural properties of nectin-3α is similar to nectin-1, it has three Ig-like domains at the extracellular region and the C-terminal conserved motif at the cytoplasmic region. The homology 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 form cis-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 called trans-hetero interaction.[7]

Function

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Most of the publications deal with nectin-3 regardless the splicing variants, thus this page follows this concept.

Role in neural system

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Nectin-3 is expressed by granule cells in dentate 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-term spatial memory and temporal order memory. It is also very probable that the nectin-3 in dentate gyrus neurons modulate adult neurogenesis and dendritic spine plasticity.[11] It has been proven that combination nectin-3/nectin-1 is very important in formation of synapses 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 the visual 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 the adhesion between the pigment and non-pigment cell layers of the ciliary epithelia, which is essential for the morphogenesis of the ciliary body of the eye.[14]

Role in gametogenesis

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Nectin-3 is important role player in spermatid development. The nectin-3–/– male mice were found to have defects in the later steps of sperm morphogenesis, exhibiting distorted nuclei and abnormal distribution of mitochondria. The loss of nectin-3 in male mice leads to male-specific infertility.[15] It has been shown that the chronic stress negatively influences the amnout of nectin-3 in the testis and also the male spermatogenesis function.[16]

Role in transendothelial migration

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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 on epithelial cells is very important in the lymphocyte transendothelial 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 also monocyte extravasation.[17]

Nectin-3 in cancer

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Nectin-3 is highly expressed in epithelial cancer cells of human lung 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 earlier relapse and death.[18] Increased amounts of nectin-3 are also detectable in ovaries during the ovarian 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 of matrix metalloproteinases (MMPs) MMP2 and MMP9 in ovarian cancer.[19]

Contrary to previously mentioned cancers, the amount of nectin-3 negatively correlates with Pancreatic neuroendocrine tumors. The loss of this protein correlates with increased tumor progressiveness.[20]

Interactions

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Nectin-3 has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000177707 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022656 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Samanta D, Almo SC (February 2015). "Nectin family of cell-adhesion molecules: structural and molecular aspects of function and specificity". Cellular and Molecular Life Sciences. 72 (4): 645–658. doi:10.1007/s00018-014-1763-4. PMC 11113404. PMID 25326769. S2CID 8927667.
  6. ^ de Agustín-Durán D, Mateos-White I, Fabra-Beser J, Gil-Sanz C (January 2021). "Stick around: Cell-Cell Adhesion Molecules during Neocortical Development". Cells. 10 (1): 118. doi:10.3390/cells10010118. PMC 7826847. PMID 33435191.
  7. ^ a b c d e f Satoh-Horikawa K, Nakanishi H, Takahashi K, Miyahara M, Nishimura M, Tachibana K, et al. (April 2000). "Nectin-3, a new member of immunoglobulin-like cell adhesion molecules that shows homophilic and heterophilic cell-cell adhesion activities". The Journal of Biological Chemistry. 275 (14): 10291–10299. doi:10.1074/jbc.275.14.10291. PMID 10744716.
  8. ^ Devilard E, Xerri L, Dubreuil P, Lopez M, Reymond N (2013-10-07). "Nectin-3 (CD113) interacts with Nectin-2 (CD112) to promote lymphocyte transendothelial migration". PLOS ONE. 8 (10): e77424. Bibcode:2013PLoSO...877424D. doi:10.1371/journal.pone.0077424. PMC 3792040. PMID 24116228.
  9. ^ Miyoshi J, Takai Y (2007). "Nectin and nectin-like molecules: biology and pathology". American Journal of Nephrology. 27 (6): 590–604. doi:10.1159/000108103. PMID 17823505. S2CID 42662486.
  10. ^ 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. PMID 18593353.
  11. ^ Wang XX, Li JT, Xie XM, Gu Y, Si TM, Schmidt MV, Wang XD (September 2017). "Nectin-3 modulates the structural plasticity of dentate granule cells and long-term memory". Translational Psychiatry. 7 (9): e1228. doi:10.1038/tp.2017.196. PMC 5639241. PMID 28872640.
  12. ^ Mizoguchi A, Nakanishi H, Kimura K, Matsubara K, Ozaki-Kuroda K, Katata T, et al. (February 2002). "Nectin: an adhesion molecule involved in formation of synapses". The Journal of Cell Biology. 156 (3): 555–565. doi:10.1083/jcb.200103113. PMC 2173327. PMID 11827984.
  13. ^ Tomorsky J, Parker PR, Doe CQ, Niell CM (2019-12-10). "Precise levels of Nectin-3 and an interaction with Afadin are required for proper synapse formation in postnatal visual cortex". bioRxiv. doi:10.1101/870691. S2CID 219723291.
  14. ^ Inagaki M, Irie K, Ishizaki H, Tanaka-Okamoto M, Morimoto K, Inoue E, et al. (April 2005). "Roles of cell-adhesion molecules nectin 1 and nectin 3 in ciliary body development". Development. 132 (7): 1525–1537. doi:10.1242/dev.01697. PMID 15728677. S2CID 24560202.
  15. ^ Inagaki M, Irie K, Ishizaki H, Tanaka-Okamoto M, Miyoshi J, Takai Y (September 2006). "Role of cell adhesion molecule nectin-3 in spermatid development". Genes to Cells. 11 (9): 1125–1132. doi:10.1111/j.1365-2443.2006.01006.x. PMID 16923130. S2CID 39799813.
  16. ^ Li T, Yao J, Zhang Q, Li Q, Li J, Wang X, et al. (April 2020). "Chronic stress impairs male spermatogenesis function and Nectin-3 protein expression in the testis". Physiological Research. 69 (2): 297–306. doi:10.33549/physiolres.934287. PMC 8565941. PMID 32324042.
  17. ^ Devilard E, Xerri L, Dubreuil P, Lopez M, Reymond N (2013-10-07). "Nectin-3 (CD113) interacts with Nectin-2 (CD112) to promote lymphocyte transendothelial migration". PLOS ONE. 8 (10): e77424. Bibcode:2013PLoSO...877424D. doi:10.1371/journal.pone.0077424. PMC 3792040. PMID 24116228.
  18. ^ Maniwa Y, Nishio W, Okita Y, Yoshimura M (May 2012). "Expression of nectin 3: Novel prognostic marker of lung adenocarcinoma". Thoracic Cancer. 3 (2): 175–181. doi:10.1111/j.1759-7714.2011.00104.x. PMID 28920296. S2CID 6861003.
  19. ^ Xu F, Si X, Wang J, Yang A, Qin T, Yang Y (February 2019). "Nectin-3 is a new biomarker that mediates the upregulation of MMP2 and MMP9 in ovarian cancer cells". Biomedicine & Pharmacotherapy. 110: 139–144. doi:10.1016/j.biopha.2018.11.020. PMID 30469078. S2CID 53764287.
  20. ^ 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. PMID 31855317. S2CID 209418057.
  21. ^ 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. PMID 11024295.
  22. ^ Takekuni K, Ikeda W, Fujito T, Morimoto K, Takeuchi M, Monden M, Takai Y (February 2003). "Direct binding of cell polarity protein PAR-3 to cell-cell adhesion molecule nectin at neuroepithelial cells of developing mouse". The Journal of Biological Chemistry. 278 (8): 5497–5500. doi:10.1074/jbc.C200707200. PMID 12515806.
  23. ^ Sakamoto Y, Ogita H, Komura H, Takai Y (January 2008). "Involvement of nectin in inactivation of integrin alpha(v)beta(3) after the establishment of cell-cell adhesion". The Journal of Biological Chemistry. 283 (1): 496–505. doi:10.1074/jbc.M704195200. PMID 17965016.
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