Structural Organization of the Porcine and Human Genes Coding for a Leydig Cell-Specific Insulin-like Peptide (LEY I-L) and Chromosomal Localization of the Human Gene (INSL3)

Burkhardt, Elke; Adham, Ibrahim M.; Brosig, Bernard; Gastmann, Anja; Matteï, Marie‐Geneviève; Engel, Wolfgang

doi:10.1006/geno.1994.1121

Cited by 92 publications

(45 citation statements)

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“…This exonic organization is similar to that for the relaxin and insulin genes. In humans, the RLF/Ley-I-L gene has been localized to the short arm of chromosome 19 (p13.2-p12; Burghardt et al, 1994b). Although studies on the regulation of the RLF gene are still very preliminary, the promoter region of the mouse gene does not appear to contain marked homology to other known genes.…”

Section: Gene and Peptide Structurementioning

confidence: 99%

Biology of the relaxin-like factor (RLF)

Ivell¹

1997

Reviews of Reproduction

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Section: Gene and Peptide Structurementioning

confidence: 99%

Biology of the relaxin-like factor (RLF)

Ivell¹

1997

Reviews of Reproduction

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“…; also known as relaxin-like factor and Leydig cell insulin-like peptide) was originally discovered and isolated as a cDNA clone from a boar testis cDNA library (1). It is primarily produced by prenatal and postnatal mature Leydig cells of the testis and the thecal cells of the ovary.…”

mentioning

confidence: 99%

Solution Structure and Characterization of the LGR8 Receptor Binding Surface of Insulin-like Peptide 3

Rosengren

Zhang

Lin

et al. 2006

Journal of Biological Chemistry

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Insulin-like peptide 3 (INSL3), a member of the relaxin peptide family, is produced in testicular Leydig cells and ovarian thecal cells. Gene knock-out experiments have identified a key biological role in initiating testes descent during fetal development. Additionally, INSL3 has an important function in mediating male and female germ cell function. These actions are elicited via its recently identified receptor, LGR8, a member of the leucine-rich repeat-containing G-protein-coupled receptor family. To identify the structural features that are responsible for the interaction of INSL3 with its receptor, its solution structure was determined by NMR spectroscopy together with in vitro assays of a series of B-chain alanine-substituted analogs. Synthetic human INSL3 was found to adopt a characteristic relaxin/insulin-like fold in solution but is a highly dynamic molecule. The four termini of this two-chain peptide are disordered, and additional conformational exchange is evident in the molecular core. Alanine-substituted analogs were used to identify the key residues of INSL3 that are responsible for the interaction with the ectodomain of LGR8. These include Arg B16 and Val B19 , with His B12 and Arg B20 playing a secondary role, as evident from the synergistic effect on the activity in double and triple mutants involving these residues. Together, these amino acids combine with the previously identified critical residue, Trp B27 , to form the receptor binding surface. The current results provide clear direction for the design of novel specific agonists and antagonists of this receptor. Insulin-like peptide 3 (INSL3 4; also known as relaxin-like factor and Leydig cell insulin-like peptide) was originally discovered and isolated as a cDNA clone from a boar testis cDNA library (1). It is primarily produced by prenatal and postnatal mature Leydig cells of the testis and the thecal cells of the ovary. Its primary structure showed it to be a bona fide member of the insulin-insulin-like growth factor-relaxin superfamily, which is now known to have a total of ten members in the human. Like insulin, INSL3 is firstly synthesized as a pre-prohormone precursor containing a signal peptide linked to B-C-A domains. It undergoes processing by hitherto unidentified proprotein convertases, resulting in the production of mature INSL3 consisting of a A-B heterodimer that is covalently linked by two interchain disulfide bonds and one intrachain disulfide bond (Fig. 1) (2). These disulfide bonds are essential for maintaining its expected characteristic insulin-like conformation and its unique biological activities (3). The receptor for INSL3, LGR8, is a member of the leucine-rich repeat-containing G-proteincoupled receptor family (4). It is closely related to the relaxin receptor, LGR7, and has been recently classified as relaxin family peptide (RXFP) receptor, RXFP2 (5). Importantly, relaxin peptides from some species can also bind to and activate LGR8, albeit with a lower affinity than INSL3 (5).Male mice homozygous with targeted disrup...

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“…Insulin-like growth factor II (IGF-II) belongs to a family of hormonally active polypeptides, also comprising IGF-I, insulin, the Leydig cell-specific insulin-like peptide (1), and relaxin (2). IGF-II circulates bound to specific IGF-binding proteins (IGFBPs) (3).…”

mentioning

confidence: 99%

Insulin-like growth factor II signaling through the insulin-like growth factor II/mannose-6-phosphate receptor promotes exocytosis in insulin-secreting cells

Zhang

Tally

Larsson

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The insulin-like growth factor II (IGF-II)͞ mannose-6-phosphate (M-6-P) receptor is known to participate in endocytosis as well as sorting of lysosomal enzymes and is involved in membrane trafficking through rapid cycling between cytosolic membrane compartments and the plasma membrane. Here we demonstrate that IGF-II, acting through the IGF-II͞M-6-P receptor, promotes exocytosis of insulin in the pancreatic ␤ cell. The effect of IGF-II was evoked at nonstimulatory concentrations of glucose, was mediated by a pertussis toxin sensitive GTP-binding protein, was dependent on protein kinase C-induced phosphorylation, and was independent of changes in cytoplasmic free Ca 2؉ concentration. Since the applied concentration of IGF-II is within the range normally found free in circulation in humans, this novel signaling pathway for the IGF-II͞M-6-P receptor is likely to be involved in modulation of insulin exocytosis under physiological conditions.

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Structural Organization of the Porcine and Human Genes Coding for a Leydig Cell-Specific Insulin-like Peptide (LEY I-L) and Chromosomal Localization of the Human Gene (INSL3)

Cited by 92 publications

References 0 publications

Biology of the relaxin-like factor (RLF)

Biology of the relaxin-like factor (RLF)

Solution Structure and Characterization of the LGR8 Receptor Binding Surface of Insulin-like Peptide 3

Insulin-like growth factor II signaling through the insulin-like growth factor II/mannose-6-phosphate receptor promotes exocytosis in insulin-secreting cells

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