# NUP214

## Overview
NUP214 is a gene that encodes the protein nucleoporin 214, a crucial component of the nuclear pore complex (NPC), which is involved in the regulation of nucleocytoplasmic transport. Nucleoporin 214 is categorized as a nucleoporin, a type of protein that forms the structural framework of the NPC, facilitating the transport of molecules between the nucleus and the cytoplasm. The protein is characterized by its complex structure, including a β-propeller domain, leucine zipper motifs, and FG-repeat motifs, which are essential for its interactions with various transport receptors (paulillo2007analysis; Mendes2019NUP214). NUP214 plays a significant role in the CRM1-dependent nuclear export pathway and interacts with several transport receptors, including CRM1 and NXF1, to mediate the export of proteins and mRNA (Hutten2006Nup214; Mendes2019NUP214). Clinically, NUP214 is implicated in hematological malignancies through chromosomal translocations, such as DEK-NUP214 and SET-NUP214, which are associated with acute myeloid leukemia and T-cell acute lymphoblastic leukemia, respectively (Van2008The; Takeda2014Nucleoporins). These translocations often result in aggressive disease phenotypes, underscoring the importance of NUP214 in both cellular transport and disease pathology.

## Structure
NUP214, or nucleoporin 214, is a component of the nuclear pore complex (NPC) and is characterized by a complex molecular structure. The protein is organized into three main domains: an N-terminal domain with a seven-bladed β-propeller structure, a central domain featuring a leucine zipper motif and coiled-coil segments, and a C-terminal domain containing FG-repeat motifs (paulillo2007analysis; Mendes2019NUP214). The β-propeller domain is formed by four antiparallel β-strands in each of the seven blades, creating a central cavity and unique structural features such as long loop insertions and a double-Velcro closure (Napetschnig2007Crystal). 

The C-terminal extension (CTE) of NUP214 binds to the bottom face of the β-propeller, involving both ionic and hydrophobic interactions, and is suggested to be dynamically regulated by phosphorylation (Napetschnig2007Crystal). NUP214 is known for post-translational modifications, including phosphorylation and O-linked N-acetylglucosamine modifications, which may influence its function (Napetschnig2007Crystal; paulillo2007analysis). The FG-repeat domain is flexible and can span both the cytoplasmic and nuclear faces of the NPC, facilitating interactions with various transport receptors (paulillo2007analysis).

## Function
NUP214, also known as nucleoporin 214, is a critical component of the nuclear pore complex (NPC) located on the cytoplasmic side. It plays a significant role in nucleocytoplasmic transport, particularly in the CRM1-dependent nuclear protein export pathway. NUP214 interacts with CRM1, the major exportin for proteins, forming a high-affinity complex necessary for the terminal steps of protein export. This interaction is facilitated by the presence of RanGTP, which stabilizes the CRM1-export complexes at the cytoplasmic filaments of the NPC, acting as a final anchoring site before disassembly and cargo release into the cytoplasm (Hutten2006Nup214; Mendes2019NUP214).

NUP214 also interacts with other transport receptors, such as NXF1, the principal mRNA export factor, and is involved in mRNA export, although its depletion results in only a modest mRNA export defect (Hutten2006Nup214; Mendes2019NUP214). Structurally, NUP214 contains multiple FG-repeats that mediate interactions with various transport receptors, and its C-terminal domain is crucial for these interactions (paulillo2007analysis). The protein is essential for maintaining efficient nuclear-cytoplasmic transport, and its disruption can lead to impaired cell proliferation and slower cell growth (Hutten2006Nup214).

## Clinical Significance
The NUP214 gene is clinically significant due to its involvement in various hematological malignancies through chromosomal translocations. One of the most studied translocations is the DEK-NUP214 fusion, resulting from t(6;9)(p23;q34), which is associated with acute myeloid leukemia (AML). This fusion is characterized by poor clinical outcomes and a high incidence of FLT3-ITD mutations (Takeda2014Nucleoporins). Another significant fusion is SET-NUP214, which arises from del(9)(q34) and is linked to T-cell acute lymphoblastic leukemia (T-ALL), acute undifferentiated leukemia, and occasionally AML. This fusion acts as a transcriptional regulator of the HOXA gene cluster, contributing to leukemogenesis by inhibiting T-cell maturation (Van2008The).

The NUP214-ABL1 fusion, found in T-ALL and B-cell precursor acute lymphoblastic leukemia (BCP-ALL), results in a constitutively activated tyrosine kinase similar to BCR-ABL1 in chronic myeloid leukemia (CML). This fusion is associated with an aggressive disease course and is sensitive to tyrosine kinase inhibitors like imatinib (Graux2004Fusion). These translocations often lead to aggressive forms of leukemia with poor survival rates, highlighting the need for targeted therapies (Mendes2019NUP214).

## Interactions
NUP214, a component of the nuclear pore complex (NPC), is involved in various protein interactions essential for nucleocytoplasmic transport. It forms a stable subcomplex with NUP88, which is crucial for their proper localization to the NPC. The depletion of NUP214 leads to the mislocalization of NUP88, indicating their interdependence (Bernad2004Nup358RanBP2). NUP214 also interacts with CRM1, a transport receptor involved in nuclear export, with this interaction being more stable in the presence of RanGTP and nuclear export signal (NES) substrates (Bernad2004Nup358RanBP2).

NUP214 interacts with the adenovirus hexon protein, facilitating the nuclear import of adenovirus DNA. This interaction is critical, as depletion of NUP214 significantly reduces hexon binding and the nuclear import of the viral genome (Cassany2015Nuclear). Additionally, NUP214 interacts with the influenza A virus NS2/NEP protein, which is involved in the nucleocytoplasmic transport of viral ribonucleoproteins (vRNPs). This interaction is essential for the nuclear export of vRNPs, as demonstrated by the suppression of viral replication upon NUP214 knockdown (ŞENBAŞ2020Interaction).

NUP214 also interacts with the Vitamin D receptor (VDR), modulating its function as a transcription factor. The full-length NUP214 enhances VDR-mediated transcriptional activation, while its carboxy-terminal fragment suppresses it (Miyauchi2009Oncogenic).


## References


[1. (Miyauchi2009Oncogenic) Yoshiteru Miyauchi, Naoko Sakaguchi, Tomoko Okada, Makoto Makishima, Keiichi Ozono, and Toshimi Michigami. Oncogenic nucleoporin can/nup214 interacts with vitamin d receptor and modulates its function. Journal of Cellular Biochemistry, 106(6):1090–1101, February 2009. URL: http://dx.doi.org/10.1002/jcb.22101, doi:10.1002/jcb.22101. This article has 5 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/jcb.22101)

[2. (Van2008The) Pieter Van Vlierberghe, Martine van Grotel, Joëlle Tchinda, Charles Lee, H. Berna Beverloo, Peter J. van der Spek, Andrew Stubbs, Jan Cools, Kyosuke Nagata, Maarten Fornerod, Jessica Buijs-Gladdines, Martin Horstmann, Elisabeth R. van Wering, Jean Soulier, Rob Pieters, and Jules P. P. Meijerink. The recurrent set-nup214 fusion as a new hoxa activation mechanism in pediatric t-cell acute lymphoblastic leukemia. Blood, 111(9):4668–4680, May 2008. URL: http://dx.doi.org/10.1182/blood-2007-09-111872, doi:10.1182/blood-2007-09-111872. This article has 173 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1182/blood-2007-09-111872)

[3. (Mendes2019NUP214) Adélia Mendes and Birthe Fahrenkrog. Nup214 in leukemia: it’s more than transport. Cells, 8(1):76, January 2019. URL: http://dx.doi.org/10.3390/cells8010076, doi:10.3390/cells8010076. This article has 45 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cells8010076)

[4. (Bernad2004Nup358RanBP2) Rafael Bernad, Hella van der Velde, Maarten Fornerod, and Helen Pickersgill. Nup358/ranbp2 attaches to the nuclear pore complex via association with nup88 and nup214/can and plays a supporting role in crm1-mediated nuclear protein export. Molecular and Cellular Biology, 24(6):2373–2384, March 2004. URL: http://dx.doi.org/10.1128/mcb.24.6.2373-2384.2004, doi:10.1128/mcb.24.6.2373-2384.2004. This article has 141 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.24.6.2373-2384.2004)

5. (paulillo2007analysis) Sara Maria Paulillo. Analysis of the functional role of nucleoporin Nup214 in nuclear transport and other cellular processes. PhD thesis, University_of_Basel, 2007. This article has 0 citations.

[6. (Takeda2014Nucleoporins) Akiko Takeda and Nabeel R. Yaseen. Nucleoporins and nucleocytoplasmic transport in hematologic malignancies. Seminars in Cancer Biology, 27:3–10, August 2014. URL: http://dx.doi.org/10.1016/j.semcancer.2014.02.009, doi:10.1016/j.semcancer.2014.02.009. This article has 37 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.semcancer.2014.02.009)

[7. (Cassany2015Nuclear) Aurélia Cassany, Jessica Ragues, Tinglu Guan, Dominique Bégu, Harald Wodrich, Michael Kann, Glen R. Nemerow, and Larry Gerace. Nuclear import of adenovirus dna involves direct interaction of hexon with an n-terminal domain of the nucleoporin nup214. Journal of Virology, 89(3):1719–1730, February 2015. URL: http://dx.doi.org/10.1128/jvi.02639-14, doi:10.1128/jvi.02639-14. This article has 56 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/jvi.02639-14)

[8. (Napetschnig2007Crystal) Johanna Napetschnig, Günter Blobel, and André Hoelz. Crystal structure of the n-terminal domain of the human protooncogene nup214/can. Proceedings of the National Academy of Sciences, 104(6):1783–1788, February 2007. URL: http://dx.doi.org/10.1073/pnas.0610828104, doi:10.1073/pnas.0610828104. This article has 55 citations.](https://doi.org/10.1073/pnas.0610828104)

[9. (Hutten2006Nup214) Saskia Hutten and Ralph H. Kehlenbach. Nup214 is required for crm1-dependent nuclear protein export in vivo. Molecular and Cellular Biology, 26(18):6772–6785, September 2006. URL: http://dx.doi.org/10.1128/mcb.00342-06, doi:10.1128/mcb.00342-06. This article has 134 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1128/mcb.00342-06)

[10. (ŞENBAŞ2020Interaction) Burçak ŞENBAŞ AKYAZ, Ayşegül PİRİNÇAL, Atsushi KAWAGUCHI, Kyosuke NAGATA, and Kadir TURAN. Interaction of influenza a virus ns2/nep protein with the amino-terminal part of nup214. TURKISH JOURNAL OF BIOLOGY, 44(2):82–92, April 2020. URL: http://dx.doi.org/10.3906/biy-1909-49, doi:10.3906/biy-1909-49. This article has 12 citations and is from a peer-reviewed journal.](https://doi.org/10.3906/biy-1909-49)

[11. (Graux2004Fusion) C. Graux, J. Cools, C. Melotte, H. Quentmeier, A. Ferrando, R. Levine, J.R. Vermeesch, M. Stul, B. Dutta, N. Boeckx, A. Bosly, P. Heimann, A. Uyttebroeck, N. Mentens, R. Somers, R.A.F. MacLeod, H.G. Drexler, A.T. Look, D.G. Gilliland, L. Michaux, P. Vandenberghe, I. Wlodarska, Peter Marynen, and Anne Hagemeijer. Fusion of nup214 to abl1 on amplified episomes in t-cell acute lymphoblastic leukemia. Nature Genetics, 36(10):1084–1089, September 2004. URL: http://dx.doi.org/10.1038/ng1425, doi:10.1038/ng1425. This article has 321 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/ng1425)