Development - S1P1 signaling pathway

S1P1 receptor signaling pathway

Sphingosine-1-phosphate receptor 1, also known as S1P1 receptor is a high affinity receptor for the bioactive lipid (2S,3R,4E)-Sphingosine 1-phosphate [1], [2]. Although the S1P1 receptor expression is very abundant in endothelial cells, transcripts related to S1P1 receptor are also detected at lower levels in vascular smooth muscle cells, fibroblasts, melanocytes, cells of epithelioid origin, brain [3], alveolar macrophages [4], cardiovascular tissues [5], natural killer cells and T cells [6].

S1P1 receptor is a G-protein coupled receptor which interacts with G-protein alpha-i1, G-protein alpha-i2 and G-protein alpha-i3 and G-protein alpha-o [7], [8].

G-protein alpha-i family members inhibit Adenylate cyclase activity. Thereby, binding of (2S,3R,4E)-Sphingosine 1-phosphate to S1P1 receptor significantly decreases Cyclic AMP level [2], [9].

(2S,3R,4E)-Sphingosine 1-phosphate binding to S1P1 receptor activates Phosphoinositide-3-kinase (PI3K)/ AKT1 cascade through G-protein alpha-i family-dependent mechanism [10]. PI3K / AKT1 pathway activation possibly occurs through G-protein beta/gamma subunits-mediated activation of c-Src which promotes formation of GAB1/ GRB2/ PI3K cat class IA (p110-alpha) complex leading to activation of PI3K pathway [11], [12], [13].

AKT1 phosphorylates the third intracellular loop of S1P1 receptor in activation-dependent manner. This event is essential for Rac1 activation [10]. Activation of PI3K/ AKT1 pathway leads to an interaction between Tiam1 with the phosphorylated S1P1 receptor. This interaction triggers Tiam1-mediated Rac1 GDP-GTP exchange [13].

Furthermore, AKT1 directly phosphorylates and activates eNOS leading to nitric oxide production [14]. AKT1 directly phosphorylates and inhibits GSK3 beta [10]. GSK3 beta inhibition results in increased cell viability [15].

VAV-1 is an important link between PI3K pathway and Rho GTPases which are necessary to promote (2S,3R,4E)-Sphingosine 1-phosphate-induced cell migration. VAV-1 activity is regulated by PI3K activation and PtdIns(3,4,5)P3 concentration. CDC42, RhoA and Rac1 are downstream targets of VAV-1 [16].

CDC42 and Rac1 regulate synthesis of Sphigosine-1-phosphate-induced cortical actin, whereas RhoA controls Sphigosine-1-phosphate-mediated stress fiber assembly, therefore promoting cell adhesion and cell motility [1], [17].

S1P1 receptor mobilizes Ca('2+) from intracellular pools through the G-protein beta/gamma mediated activation of PLC-beta and IP3 [9]. Ca('2+) release, possibly, promotes lymphangiogenesis [18].

CD69 forms a complex with S1P1 receptor, inhibiting function of S1P1 receptor receptor in lymphocyte egress [19].

CD44 association with S1P1 receptor induces transactivation of the latter receptor via its AKT1-dependent threonine phosphorylation. Consequent S1P1 receptor-induced Rac1 signaling leads to cortical actin thickening and barrier enhancement [20].

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References:

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