LANCL2

LANCL2
Identifiers
Aliases	LANCL2 , GPR69B, TASP, LanC like 2
External IDs	OMIM: 612919; MGI: 1919085; HomoloGene: 23116; GeneCards: LANCL2; OMA:LANCL2 - orthologs
Gene location (Human) Chr. Chromosome 7 (human) [1] Band 7p11.2 Start 55,365,337 bp [1] End 55,433,737 bp [1]
Gene location (Mouse) Chr. Chromosome 6 (mouse) [2] Band 6|6 B3 Start 57,679,525 bp [2] End 57,716,424 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in middle temporal gyrus lateral nuclear group of thalamus gonad entorhinal cortex postcentral gyrus superior frontal gyrus prefrontal cortex Brodmann area 23 sperm endothelial cell Top expressed in spermatocyte spermatid seminiferous tubule subiculum barrel cortex genital tubercle medial ganglionic eminence prefrontal cortex facial motor nucleus tail of embryo More reference expression data BioGPS More reference expression data
Gene ontology Molecular function phosphatidylinositol-4-phosphate binding phosphatidylinositol-5-phosphate binding GTP binding protein binding ATP binding phosphatidylinositol-3-phosphate binding catalytic activity Cellular component cytosol plasma membrane membrane nucleus cortical actin cytoskeleton cytoplasm Biological process positive regulation of abscisic acid-activated signaling pathway negative regulation of transcription, DNA-templated Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 55915 71835 Ensembl ENSG00000132434 ENSMUSG00000062190 UniProt Q9NS86 Q9JJK2 RefSeq (mRNA) NM_018697 NM_133737 RefSeq (protein) NP_061167 NP_598498 Location (UCSC) Chr 7: 55.37 – 55.43 Mb Chr 6: 57.68 – 57.72 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

LanC-like protein 2 is a protein that in humans is encoded by the LANCL2 gene. ^{[5] [6]} It is a protein broadly expressed in the plasma a nuclear membranes of immune, epithelial and muscle cells and a potential therapeutic target for chronic inflammatory, metabolic and immune-mediated diseases such as Crohn's disease and diabetes. ^[7]

Function

The natural ligand of LANCL2, abscisic acid (ABA), has been identified as a new endogenous mammalian hormone implicated in glycemic control. The mammalian ABA receptor has been identified as LANCL2 on the basis of (1) modeling predictions, ^[8] (2) direct and specific ABA binding to the purified recombinant protein, ^[9] and (3) abrogation of the functional effects of ABA by silencing of LANCL2 expression in ABA-sensitive cells. ^[10]

Selective binding between LANCL2 and ABA or other ligands such as the benzimidazole NSC61610 and piperazine BT-11, ^[11] lead to elevation of intracellular cAMP, activation of PKA ^[12] and suppression of inflammation ^[12] in macrophages. In hepatocytes, LANCL2 regulates cell survival by phosphorylation of Akt through its interaction with the Akt kinase mTORC2. ^[13] Active mTORC2 causes translocation of GLUT4 to the plasma membrane and stimulates glucose uptake. ^[14] LANCL2 expression in immune cells, adipose tissue, skeletal muscle and pancreas, and the potential to manipulate LANCL2 signaling and GLUT4 translocation with ABA make this G protein-coupled receptor a novel therapeutic target for glycemic control. ^[7] In humans, ABA release was detected with increasing glycemia, although this mechanism failed in people suffering from type 2 and gestational diabetes. Also, plasma ABA concentrations increase after oral glucose load (OGTT) in healthy subjects. ^[15] ABA stimulates glucose-dependent insulin release from human and rodent pancreatic β-cells. ^[15] At a low dose (micrograms/Kg body weight) oral ABA significantly reduces both glycemia and insulinemia in rats and in humans undergoing an OGTT ^[16] indicating that ABA reduces the amount of insulin required to control hyperglycemia. This insulin-sparing effect suggests that LANCL2 can be used as a therapeutic target for the treatment of inflammatory and metabolic diseases such as metabolic syndrome, prediabetes and diabetes.

Novel LANCL2 ligands such as BT-11 significantly decrease disease activity in the Dextran Sodium Sulfate (DSS)-induced model of acute colitis and the IL-10-/- mice and CD4+ T cell transfer-induced chronic colitis models. ^[11] BT-11 treatment decreased leukocytic infiltration, mucosal thickening and epithelial erosion in the colon, decreased Th1 and Th17 CD4+ T cells and TNFα while increasing regulatory T cells, LANCL2 and IL-10 expression. ^[11]

Activators

• Omilancor

References

1. GRCh38: Ensembl release 89: ENSG00000132434 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000062190 – 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. Mayer H, Pongratz M, Prohaska R (Dec 2001). "Molecular cloning, characterization, and tissue-specific expression of human LANCL2, a novel member of the LanC-like protein family". DNA Sequence. 12 (3): 161–6. doi:10.3109/10425170109080770. PMID   11762191. S2CID   43695440.
6. "Entrez Gene: LANCL2 LanC lantibiotic synthetase component C-like 2 (bacterial)".
7. Lu P, Hontecillas R, Philipson CW, Bassaganya-Riera J (Jun 2014). "Lanthionine synthetase component C-like protein 2: a new drug target for inflammatory diseases and diabetes". Current Drug Targets. 15 (6): 565–72. doi:10.2174/1389450115666140313123714. PMID   24628287.
8. Lu P, Bevan DR, Lewis SN, Hontecillas R, Bassaganya-Riera J (Mar 2011). "Molecular modeling of lanthionine synthetase component C-like protein 2: a potential target for the discovery of novel type 2 diabetes prophylactics and therapeutics". Journal of Molecular Modeling. 17 (3): 543–53. doi:10.1007/s00894-010-0748-y. PMID   20512604. S2CID   22559285.
9. Sturla L, Fresia C, Guida L, Grozio A, Vigliarolo T, Mannino E, Millo E, Bagnasco L, Bruzzone S, De Flora A, Zocchi E (Nov 2011). "Binding of abscisic acid to human LANCL2". Biochemical and Biophysical Research Communications. 415 (2): 390–5. doi:10.1016/j.bbrc.2011.10.079. PMID   22037458.
10. Sturla L, Fresia C, Guida L, Bruzzone S, Scarfì S, Usai C, Fruscione F, Magnone M, Millo E, Basile G, Grozio A, Jacchetti E, Allegretti M, De Flora A, Zocchi E (Oct 2009). "LANCL2 is necessary for abscisic acid binding and signaling in human granulocytes and in rat insulinoma cells". The Journal of Biological Chemistry. 284 (41): 28045–57. doi: 10.1074/jbc.M109.035329 . PMC   2788856 . PMID   19667068.
11. "Lanthionine synthetase C-like 2: A novel therapeutic target for inflammatory bowel disease | NIMML". www.nimml.org. Retrieved 2016-02-09.
12. Bassaganya-Riera J, Guri AJ, Lu P, Climent M, Carbo A, Sobral BW, Horne WT, Lewis SN, Bevan DR, Hontecillas R (Jan 2011). "Abscisic acid regulates inflammation via ligand-binding domain-independent activation of peroxisome proliferator-activated receptor gamma". The Journal of Biological Chemistry. 286 (4): 2504–16. doi: 10.1074/jbc.M110.160077 . PMC   3024745 . PMID   21088297.
13. Zeng M, van der Donk WA, Chen J (Dec 2014). "Lanthionine synthetase C-like protein 2 (LanCL2) is a novel regulator of Akt". Molecular Biology of the Cell. 25 (24): 3954–61. doi:10.1091/mbc.E14-01-0004. PMC   4244203 . PMID   25273559.
14. Sato M, Dehvari N, Oberg AI, Dallner OS, Sandström AL, Olsen JM, Csikasz RI, Summers RJ, Hutchinson DS, Bengtsson T (Dec 2014). "Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle". Diabetes. 63 (12): 4115–29. doi: 10.2337/db13-1860 . PMID   25008179.
15. Bruzzone S, Ameri P, Briatore L, Mannino E, Basile G, Andraghetti G, Grozio A, Magnone M, Guida L, Scarfì S, Salis A, Damonte G, Sturla L, Nencioni A, Fenoglio D, Fiory F, Miele C, Beguinot F, Ruvolo V, Bormioli M, Colombo G, Maggi D, Murialdo G, Cordera R, De Flora A, Zocchi E (Mar 2012). "The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts". FASEB Journal. 26 (3): 1251–60. doi: 10.1096/fj.11-190140 . PMID   22075645. S2CID   19413693.
16. Magnone M, Ameri P, Salis A, Andraghetti G, Emionite L, Murialdo G, De Flora A, Zocchi E (Dec 2015). "Microgram amounts of abscisic acid in fruit extracts improve glucose tolerance and reduce insulinemia in rats and in humans". FASEB Journal. 29 (12): 4783–93. doi: 10.1096/fj.15-277731 . PMID   26243865. S2CID   9371779.

Further reading

• Park S, James CD (Feb 2003). "Lanthionine synthetase components C-like 2 increases cellular sensitivity to adriamycin by decreasing the expression of P-glycoprotein through a transcription-mediated mechanism". Cancer Research. 63 (3): 723–7. PMID   12566319.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID   9373149.
• Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID   8125298.