NELL2

NELL2
Identifiers
Aliases	NELL2, NRP2, neural EGFL like 2
External IDs	OMIM: 602320; MGI: 1858510; HomoloGene: 4488; GeneCards: NELL2; OMA:NELL2 - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q12 Start 44,508,275 bp[1] End 44,921,848 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 E3 Start 94,973,111 bp[2] End 95,426,440 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in middle temporal gyrus Brodmann area 23 retinal pigment epithelium orbitofrontal cortex frontal pole superior frontal gyrus endothelial cell Brodmann area 10 germinal epithelium postcentral gyrus Top expressed in dentate gyrus of hippocampal formation granule cell primary visual cortex superior frontal gyrus medial dorsal nucleus CA3 field perirhinal cortex piriform cortex entorhinal cortex Region I of hippocampus proper medial geniculate nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding protein binding protein kinase C binding heparin binding Cellular component extracellular region cytoplasm Biological process neuron cellular homeostasis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4753 54003 Ensembl ENSG00000184613 ENSMUSG00000022454 UniProt Q99435 Q61220 RefSeq (mRNA) NM_001145107 NM_001145108 NM_001145109 NM_001145110 NM_006159 NM_001289653 NM_016743 NM_001356950 NM_001356951 RefSeq (protein) NP_001138579 NP_001138580 NP_001138581 NP_001138582 NP_006150 NP_001276582 NP_001343879 NP_001343880 Location (UCSC) Chr 12: 44.51 – 44.92 Mb Chr 15: 94.97 – 95.43 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Protein kinase C-binding protein NELL2 is a secreted glycoprotein that in humans is encoded by the NELL2 gene.^[5] It is a homolog of Nel, which is a gene present in the neural tissues of chickens.^[6]

This gene encodes a cytoplasmic protein that contains six epidermal growth factor (EGF) -like repeats. The encoded heterotrimeric protein may be involved in cell growth regulation and differentiation. A similar protein in rodents is involved in craniosynostosis. An alternative splice variant has been described but its full length sequence has not been determined.^[5]

Function

NELL2 has been implicated to be involved in a variety of different functions including neuronal development, sperm maturation, cancer progression and bone development.^{[7][8][9][10]}

NELL2 has been shown to have roles in neuronal polarization and axon growth.^[11] NELL2 is a negative regulator of axon guidance in the SLIT-ROBO signalling pathway where it binds with the ROBO3/Rig-1 receptor.^[12] It can also bind with ROBO2 under acidic conditions, where ROBO2 undergoes proteolytic cleavage.^[8]

NELL2 expression has been linked to higher survival rates for female lung adenocarcinoma patients.^[13]

References

1. GRCh38: Ensembl release 89: ENSG00000184613 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000022454 – 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. "Entrez Gene: NELL2 NEL-like 2 (chicken)".
6. Watanabe, Takeshi K.; Katagiri, Toyomasa; Suzuki, Mikio; Shimizu, Fumio; Fujiwara, Tsutomu; Kanemoto, Naohide; Nakamura, Yusuke; Hirai, Yoshikatsu; Maekawa, Hiroumi; Takahashi, Ei-ichi (1996-12-15). "Cloning and Characterization of Two Novel Human cDNAs (NELL1 and NELL2) Encoding Proteins with Six EGF-like Repeats". Genomics. 38 (3): 273–276. doi:10.1006/geno.1996.0628. ISSN 0888-7543.
7. Miyaguchi, Masaki; Nakanishi, Yoichi; Maturana, Andrés D.; Mizutani, Kimihiko; Niimi, Tomoaki (2022-10-15). "Conformational Change of the Hairpin-like-structured Robo2 Ectodomain Allows NELL1/2 Binding". Journal of Molecular Biology. 434 (19) 167777. doi:10.1016/j.jmb.2022.167777. ISSN 0022-2836.
8. Yamamoto, Naoka; Kashiwagi, Manabu; Ishihara, Manami; Kojima, Takaaki; Maturana, Andrés D.; Kuroda, Shun'ichi; Niimi, Tomoaki (2019-03-22). "Robo2 contains a cryptic binding site for neural EGFL-like (NELL) protein 1/2". Journal of Biological Chemistry. 294 (12): 4693–4703. doi:10.1074/jbc.RA118.005819. ISSN 0021-9258. PMC 6433047. PMID 30700556.
9. Yuan, Hairui; Wang, Xinyu; Du, Shuanglin; Li, Mengyue; Zhu, Endong; Zhou, Jie; Dong, Yuan; Wang, Shuang; Shan, Liying; Liu, Qian; Wang, Baoli (2025-04-11). "NELL2, a novel osteoinductive factor, regulates osteoblast differentiation and bone homeostasis through fibronectin 1/integrin-mediated FAK/AKT signaling". Bone Research. 13 (1): 46. doi:10.1038/s41413-025-00420-5. ISSN 2095-6231. PMC 11986068. PMID 40210857.
10. Kiyozumi, Daiji; Noda, Taichi; Yamaguchi, Ryo; Tobita, Tomohiro; Matsumura, Takafumi; Shimada, Kentaro; Kodani, Mayo; Kohda, Takashi; Fujihara, Yoshitaka; Ozawa, Manabu; Yu, Zhifeng; Miklossy, Gabriella; Bohren, Kurt M.; Horie, Masato; Okabe, Masaru (2020-06-05). "NELL2-mediated lumicrine signaling through OVCH2 is required for male fertility". Science. 368 (6495): 1132–1135. Bibcode:2020Sci...368.1132K. doi:10.1126/science.aay5134. PMC 7396227. PMID 32499443.
11. Kim, Han Rae; Kim, Dong Hee; An, Ji Young; Kang, Dasol; Park, Jeong Woo; Hwang, Eun Mi; Seo, Eun Jin; Jang, Il Ho; Ha, Chang Man; Lee, Byung Ju (2020-06-30). "NELL2 Function in Axon Development of Hippocampal Neurons". Molecules and Cells. 43 (6): 581–589. doi:10.14348/molcells.2020.0032. ISSN 0219-1032. PMC 7332358. PMID 32597395.
12. Jaworski, Alexander; Tom, Irene; Tong, Raymond K.; Gildea, Holly K.; Koch, Alexander W.; Gonzalez, Lino C.; Tessier-Lavigne, Marc (2015-11-20). "Operational redundancy in axon guidance through the multifunctional receptor Robo3 and its ligand NELL2". Science. 350 (6263): 961–965. doi:10.1126/science.aad2615.
13. "Research update from the MCM team (October 2025)". World Community Grid. 28 October 2025. Retrieved 29 October 2025.

Further reading

• Watanabe TK, Katagiri T, Suzuki M, et al. (1997). "Cloning and characterization of two novel human cDNAs (NELL1 and NELL2) encoding proteins with six EGF-like repeats". Genomics. 38 (3): 273–6. doi:10.1006/geno.1996.0628. PMID 8975702.
• Beckmann G, Hanke J, Bork P, Reich JG (1998). "Merging extracellular domains: fold prediction for laminin G-like and amino-terminal thrombospondin-like modules based on homology to pentraxins". J. Mol. Biol. 275 (5): 725–30. doi:10.1006/jmbi.1997.1510. PMID 9480764.
• Luce MJ, Burrows PD (1999). "The neuronal EGF-related genes NELL1 and NELL2 are expressed in hemopoietic cells and developmentally regulated in the B lineage". Gene. 231 (1–2): 121–6. doi:10.1016/S0378-1119(99)00093-1. PMID 10231576.
• Kuroda S, Oyasu M, Kawakami M, et al. (1999). "Biochemical characterization and expression analysis of neural thrombospondin-1-like proteins NELL1 and NELL2". Biochem. Biophys. Res. Commun. 265 (1): 79–86. Bibcode:1999BBRC..265...79K. doi:10.1006/bbrc.1999.1638. PMID 10548494.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Zhang Z, Henzel WJ (2005). "Signal peptide prediction based on analysis of experimentally verified cleavage sites". Protein Sci. 13 (10): 2819–24. doi:10.1110/ps.04682504. PMC 2286551. PMID 15340161.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Lim J, Hao T, Shaw C, et al. (2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–14. doi:10.1016/j.cell.2006.03.032. PMID 16713569. S2CID 13709685.