Abstract
Gangliosides are essential components of cell membranes and are involved in a variety of physiological processes, including cell growth, differentiation, and receptor-mediated signal transduction. They regulate functions of proteins in membrane microdomains, notably receptor tyrosine kinases such as insulin receptor (InsR) and epidermal growth factor receptor (EGFR), through lateral association. Studies during the past two decades using knockout (KO) or pharmacologically inhibited cells, or KO mouse models for glucosylceramide synthase (GCS; Ugcg), GM3 synthase (GM3S; St3gal5), and GD3 synthase (GD3S; St8sia1) have revealed essential roles of gangliosides in hypothalamic control of energy balance. The a-series gangliosides GM1 and GD1a interact with leptin receptor (LepR) and promote LepR signaling through activation of the JAK2/STAT3 pathway. Studies of GM3S KO cells have shown that the extracellular signal-regulated kinase (ERK) pathway, downstream of the LepR signaling pathway, is also modulated by gangliosides. Recent studies have revealed crosstalk between the LepR signaling pathway and other receptor signaling pathways (e.g., InsR and EGFR pathways). Gangliosides thus have the ability to modulate the effects of leptin by regulating functions of such receptors, and by direct interaction with LepR to control signaling.
Highlights
Gangliosides (glycosphingolipids (GSLs) that contain one or more sialic acids) are essential components of membrane microdomains, and play key roles in a variety of important biological processes, including cell growth, differentiation, and signal transduction [1]
Gangliosides are involved in functioning of numerous growth factor receptors and hormone receptors, including epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), hepatocyte growth factor receptor (c-Met), nerve growth factor receptor (TrkA), insulin receptor (InsR), and insulin-like growth factor 1 receptor (IGF1R) [2]
Mice with POMC neuron-specific or neuronal-specific deletion of SHP2 display the obese phenotype [29,30]. These findings indicate the importance of the LepRb-SHP2-extracellular signal-regulated kinase (ERK) pathway for regulation of energy balance
Summary
Gangliosides (glycosphingolipids (GSLs) that contain one or more sialic acids) are essential components of membrane microdomains, and play key roles in a variety of important biological processes, including cell growth, differentiation, and signal transduction [1]. LepRb-expressing neuron-specific deletion of STAT3 results in the obese phenotype; the mice are fertile and display enhanced linear growth [22,23]. These observations indicate that STAT3 is a key mediator of leptin activity and essential for energy balance but is not required for growth or reproduction. Mice with a substitution mutation of Tyr985 are lean and ( in females) resistant to diet-induced obesity (DIO) [31] These Tyr985 mutant mice display reduced hypothalamic expression of Agrp and Npy, and increased leptin sensitivity resulting from suppressed SOCS3 binding to LepRb, reflecting the primary role of SOCS3 in feedback inhibition of LepRb. In regard to the LepRb-SHP2-ERK pathway, the role of SOCS3 is not reflected by the phenotype of Tyr985 mutant mice. Precise sequences that mediate specific signals will be identified in future studies
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