LanC-like protein 2 is a protein that in humans is encoded by the LANCL2gene.[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]
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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. PMID11762191. S2CID43695440.
^ abLu 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. PMID24628287.
^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. PMID20512604. S2CID22559285.
^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. PMID22037458.
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. PMID12566319.
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. PMID9373149.
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. PMID8125298.
