Abstract
The insulin-like growth factor-1 (IGF-1) signaling pathway is crucial for the regulation of growth and development. The correct processing of the IGF-1Ea prohormone (proIGF-1Ea) and the IGF-1 receptor (IGF-1R) peptide precursor requires proper N-glycosylation. Deficiencies of N-linked glycosylation lead to a clinically heterogeneous group of inherited diseases called Congenital Disorders of Glycosylation (CDG). The impact of N-glycosylation defects on IGF-1/IGF-1R signaling components is largely unknown. In this study, using dermal fibroblasts from patients with different CDG [PMM2-CDG (n = 7); ALG3-CDG (n = 2); ALG8-CDG (n = 1); GMPPB-CDG (n = 1)], we analyzed the glycosylation pattern of the proIGF-1Ea, IGF-1 secretion efficiency and IGF-1R signaling activity. ALG3-CDG, ALG8-CDG, GMPPB-CDG and some PMM2-CDG fibroblasts showed hypoglycosylation of the proIGF-1Ea and lower IGF-1 secretion when compared with control (CTR). Lower IGF-1 serum concentration was observed in ALG3-CDG, ALG8-CDG and in some patients with PMM2-CDG, supporting our in vitro data. Furthermore, reduced IGF-1R expression level was observed in ALG3-CDG, ALG8-CDG and in some PMM2-CDG fibroblasts. IGF-1-induced IGF-1R activation was lower in most PMM2-CDG fibroblasts and was associated with decreased ERK1/2 phosphorylation as compared to CTR. In general, CDG fibroblasts showed a slight upregulation of Endoplasmic Reticulum (ER) stress genes compared with CTR, uncovering mild ER stress in CDG cells. ER-stress-related gene expression negatively correlated with fibroblasts IGF-1 secretion. This study provides new evidence of a direct link between N-glycosylation defects found in CDG and the impairment of IGF-1/IGF-1R signaling components. Further studies are warranted to determine the clinical consequences of reduced systemic IGF-1 availability and local activity in patients with CDG.
Highlights
The insulin-like growth factor-1 (IGF-1) signaling pathway is fundamental for growth regulation, especially in childhood, while playing a central role in development and metabolic homeostasis
The two fibroblasts from ALG3-Congenital Disorders of Glycosylation (CDG) presented a distinct band of about 14 kDa, while ALG8-CDG and GMPPB-CDG revealed a marked accumulation of 12 kDa proteins
Among PMM2CDG fibroblasts analyzed, there was a general preservation of proIGF-1Ea N-glycosylation pattern, the IGF-1 bands intensity in PMM2_p1-CDG, PMM2_p6-CDG and PMM2_p7-CDG fibroblasts were lower compared to CTR
Summary
The insulin-like growth factor-1 (IGF-1) signaling pathway is fundamental for growth regulation, especially in childhood, while playing a central role in development and metabolic homeostasis. IGF-1 circulates primarily as part of a 150 kDa ternary complex with two additional proteins, the IGF binding protein-3 (IGFBP-3) and the acid-labile subunit (ALS). This system extends the half-life of circulating IGF-1 from 10 to 12 min to about 15 h, preserving stable serum levels of IGF-1 [1, 2]. Tissue-specific IGF-1 knockout models demonstrated the role of circulating IGF-1 in regulation of body size and tissue growth and revealed autocrine actions in specific tissues such as skeletal muscle [4], bone [5] and nervous system [6]. The activity of IGF-1 is due to a combination of local expression together with IGF-1 delivered to the tissue from the circulation where high levels are maintained [7]
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