胰岛素样生长因子(Insulin-like growth factors, IGFs)信号系统是动物体内一条重要的信号通路,广泛作用于机体的生长、发育以及疾病的发生和发展等各种生命活动过程。尽管IGFs系统的各种配体、受体和结合蛋白分子的基因结构、功能及作用机制已被深入地研究,但是有关胰岛素样生长因子酸不稳定亚基(Insulin-like growth factor acid-labile subunit, IGFALS)的功能研究却一直局限于其延长IGFs半衰期方面。近年来,越来越多的研究表明IGFALS基因的突变和蛋白表达量的偏低均可能导致动物体生长发育的延迟甚至缺陷。本文综述了IGFALS基因序列特征、IGFALS蛋白的结构特点及其生物学功能以及表达调控的研究进展,旨在为IGFALS的功能及其作用机制的深入研究提供参考。
Insulin-like growth factors (IGFs) act as a critical signaling pathway in animals and play significant roles in body growth, development, and occurrence and progression of animal diseases. In the past, structural and functional studies of ligands, receptors and even specific binding proteins in the IGFs system have been extensively investigated. However, the functional study of insulin-like growth factor acid-labile subunit (IGFALS) mainly focused on the prolonging half-life of IGFs. Increasing number of studies indicated that mutations in the IGFALS DNA sequence and low expression level of IGFALS proteins can lead to growth and development retardation in animals. In this review, we summarize recent structural and functional studies of IGFALS in mammals, aiming to further identify detailed genetic mechanism of IGFALS.
[1] Schlupf J, Steinbeisser H. IGF antagonizes the Wnt/β-Catenin pathway and promotes differentiation of extra-embryonic endoderm. Differentiation , 2014, 87(5): 209-219.
[2] Constância M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A, Fundele R, Stewart F, Kelsey G, Fowden A, Sibley C, Reik W. Placental-specific IGF-II is a major modulator of placental and fetal growth. Nature , 2002, 417(6892): 945-948.
[3] Wang YM, Nishida S, Sakata T, Elalieh HZ, Chang WH, Halloran BP, Doty SB, Bikle DD. Insulin-like growth factor-I is essential for embryonic bone development. Endocrinology , 2006, 147(10): 4753-4761.
[4] Chen L, Jiang W, Huang JY, He BC, Zuo GW, Zhang WL, Luo Q, Shi Q, Zhang BQ, Wagner ER, Luo JY, Tang M, Wietholt C, Luo XJ, Bi Y, Su YX, Liu B, Kim SH, He CJ, Hu YW, Shen JK, Rastegar F, Huang EY, Gao YH, Gao JL, Zhou JZ, Reid RR, Luu HH, Haydon RC, He TC, Deng ZL. Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation. J Bone Miner Res , 2010, 25(11): 2447-2459.
[5] Ibrahim YH, Yee D. Insulin-like growth factor-I and cancer risk. Growth Horm IGF Res , 2004, 14(4): 261-269.
[6] Ren J, Anversa P. The insulin-like growth factor I system: physiological and pathophysiological implication in cardiovascular diseases associated with metabolic syndrome. Biochem Pharmacol , 2015, 93(4): 409-417.
[7] Guler HP, Zapf J, Schmid C, Froesch ER. Insulin-like growth factors I and II in healthy man. Estimations of half-lives and production rates. Acta Endocrinol (Copenh) , 1989, 121(6): 753-758.
[8] Zapf J. Insulinlike growth factor binding proteins and tumor hypoglycemia. Trends Endocrinol Met , 1995, 6(2): 37-42.
[9] Leong SR, Baxter RC, Camerato T, Dai J, Wood WI. Structure and functional expression of the acid-labile subunit of the insulin-like growth factor-binding protein complex. Mol Endocrinol , 1992, 6(6): 870-876.
[10] Boisclair YR, Rhoads RP, Ueki I, Wang J, Ooi GT. The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system. J Endocrinol , 2001, 170(1): 63-70.
[11] Dai J, Baxter RC. Molecular cloning of the acid-labile subunit of the rat insulin-like growth factor binding protein complex. Biochem Biophys Res Commun , 1992, 188(1): 304-309.
[12] Boisclair YR, Seto D, Hsieh S, Hurst KR, Ooi GT. Organization and chromosomal localization of the gene encoding the mouse acid labile subunit of the insulin-like growth factor binding complex. Proc Natl Acad Sci USA , 1996, 93(19): 10028-10033.
[13] Rhoads RP, Greenwood PL, Bell AW, Boisclair YR. Organization and regulation of the gene encoding the sheep acid-labile subunit of the 150-kilodalton insulin-like growth factor-binding protein complex. Endocrinology , 2000, 141(4): 1425-1433.
[14] Li S, Ren JF, Huang L. Characterization of the porcine insulin- like growth factor-binding protein , acid-labile subunit gene: full-length cDNA and DNA sequence, polymorphisms and expression profile. J Anim Breed Genet , 2007, 124(3): 133-138.
[15] Kim JW, Rhoads RP, Segoale N, Kristensen NB, Bauman DE, Boiselair YR. Isolation of the cDNA encoding the acid labile subunit (ALS) of the 150 kDa IGF-binding protein complex in cattle and ALS regulation during the transition from pregnancy to lactation. J Endocrinol , 2006, 189(3): 583-593.
[16] Lee DH, Chun C, Kim SH, Lee CY. Expression of porcine acid-labile subunit (pALS) of the 150-kilodalton ternary insulin-like growth factor complex and initial characterization of recombinant pALS protein. J Biochem Mol Biol , 2005, 38(2): 225-231.
[17] Janosi JB, Firth SM, Bond JJ, Baxter RC, Delhanty PJ. N-Linked glycosylation and sialylation of the acid-labile subunit. Role in complex formation with insulin-like growth factor (IGF)-binding protein-3 and the IGFs. J Biol Chem , 1999, 274(9): 5292-5298.
[18] Baxter RC, Martin JL, Beniac VA. H