Pull the Trigger, it Fires: The Critical Role of Insulin-Stimulated Caveolin-1 Tyrosine 14 Phosphorylation in Regulation of Insulin Trans-Endothelial Transport

Abstract

EditorialIn order for insulin to exert its biological actions on target cells in peripheral tissues like muscle and adipose tissues, Insulin must pass through the endothelial barrier into the interstitium.Insulin's transendothelial transport (TET), particularly in muscle where capillaries are lined by a continuous endothelium, determines tissue insulin levels, and thereby critically determines insulin's metabolic effects [1][2][3][4][5][6]. This process is significantly impaired in insulin resistance states such as obesity and type 2 diabetes [2,[7][8][9]. Current evidence obtained by us and others indicate that insulin TET is transcellular process and mediated by transporting caveolae that contain or associate with multiple structural and signaling molecules including the insulin receptor (IR), IGF-1receptor, caveolin-1, dynamin-2, actin filaments and eNOS [10][11][12][13][14][15][16][17][18]. Among these components, caveolae and its key structural protein caveolin-1 have been shown to serve as the center to organize the molecular transcytotic machinery mediating insulin TET [13]. We have demonstrated that insulin, through its signaling pathways in the endothelium, facilitates its own movement across the endothelial cells [15]. Very recently, we reported that eNOS and its activity play a critical role in regulation of insulin uptake and TET as inhibition of eNOS activity completely eliminates endothelial insulin uptake and TET [16]. Next critical question we would ask is how insulin intracellular signaling stimulates and coordinates the assembling of the molecular machinery for insulin trans-endothelial transport? A study just published by us has provided a clue to this puzzle, i.e. insulin stimulated caveolin-1 tyrosine 14 phosphorylation severs a trigger to possibly initiate insulin TET [19].Caveolae are abundant in microvasculature [20] and represent >95% of the endothelial cell vesicles [21]. Caveolin-1 is the main structural unit and biological marker of endothelial caveolae. Caveolin-1 is required for the formation of caveolae in vascular endothelium as either targeted deletion of the gene for caveolin-1 (Cav-1-/-) [22] or knockdown of caveolin-1 expression using specific siRNA [23] results in the loss of caveolae.In contrast, expression of exogenous caveolin-1 in lymphocytes (which are normally devoid of caveolae) induces the de novo formation of caveolae, and the level of caveolin-1 expression directly correlated to the number of caveolae [24]. Early studies have shown that binding of protein macromolecules to their receptors on the cell surface induced a caveolae-mediated endocytosis whereby caveolae, as a transporting carrier, can efficiently mediate the transcellular transport of a variety of plasma proteins through the endothelial barrier [25][26][27]. While it would seem desirable to examine the role of caveolin-1 in mediating insulin TET using caveolin-1 (-/-) knockout mice, lack of caveolin-1 has been shown to induce a paracellular leak of macromolecules attributed to the loss of the tonic caveol...