Sphingosine Kinase-1 Associates with Integrin αVβ3 to Mediate Endothelial Cell Survival

Abstract

3 ECM and GF-induced survival signals involve integrins, a family of transmembrane heterodimeric cell surface proteins that are formed by two noncovalently associated subunits, ␣ and ␤. Integrins exist in two distinct functional states, an inactive nonadhesion-promoting state and a ligand-bound, active, and adhesion-promoting conformation. 4 On ligand binding, integrins are aggregated in transmembrane complexes (focal contacts) that are enriched in cytoskeletal proteins (eg, talin and vinculin) as well as signaling proteins (eg, focal adhesion kinase [FAK]) (reviewed in Refs. 5,6). Integrin ␣ v ␤ 3 is key to EC survival because disruption of ␣ v ␤ 3 ligation inhibits blood vessel formation and initiates apoptosis 7 and is also found at its highest levels on angiogenic ECs in wounds and tumors.8 GF receptors also collaborate with integrins by partitioning into common complexes within which they become activated and signal more efficiently. 9,10 Sphingosine kinase (SK) is a lipid kinase that catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate (S1P) (reviewed in Ref. 11). SK has two isoforms (SK-1 and -2), and although most cells can synthesize S1P, large amounts are present in platelets 12 and recent reports have identified erythrocytes as well as vascular endothelium as major contributors of S1P in circulation.13-15 S1P can act extracellularly through the G protein-coupled S1P receptors (S1P 1-5 ). Mature ECs express S1P receptors S1P 1-3 , and these ligand/receptor interactions promote EC survival, migration, proliferation, adherens junction assembly, increased revascularization, and wound healing both in vitro and in vivo (reviewed

Tumor Necrosis Factor-Induced Neutrophil Adhesion Occurs Via Sphingosine Kinase-1-Dependent Activation of Endothelial α5β1 Integrin

“…18 We have recently demonstrated a requirement of SK-1 phosphorylation at serine 225 for increased heterotrimeric complex formation between SK-1, ␣ v ␤ 3 and CD31 following factor deprivation where ␣ v ␤ 3 activation and subsequent EC survival signals include the Bcl-X and nuclear factor B pathways. 19 Herein we demonstrate, for the first time, that SK-1 is integral for TNF␣-induced ␣ 5 ␤ 1 activation, Ang-2 expression and neutrophil adhesion under shear flow. Whether phosphorylation of SK-1 is also involved in this process is still to be determined.…”

“…This inhibition was not observed with the ␣ v ␤ 3 blocking antibody (LM609) (Figure 6B), an integrin also activated by SK-1. 19 As TNF␣ is also known to regulate VCAM-1 and ICAM-1 expression on HUVECs via SK-1, 20 we next investigated their contribution to ␣ 5 ␤ 1 -mediated leukocyte adhesion. As shown in Figure 6B, antibodies to ␣ 5 ␤ 1 , VCAM-1 and ICAM-1, alone, or together, demonstrated a similar level of inhibition.…”

“…18 More recently we observed that SK-1 activates ␣ v ␤ 3 integrin to mediate EC survival signaling pathway via formation of a heterotrimeric complex between SK-1, ␣ v ␤ 3 and CD31. 19 In ECs, TNF␣-induced up-regulation of E-selectin, VCAM-1 and ICAM-1 expression is an SK-1-dependent process. 20,21 Together, it is tempting to speculate that SK-1 may also contribute to integrin-mediated leukocyte adhesion under shear stress, and as such, act as a master switch for adhesion molecules and thus become a single target for therapeutic intervention.…”

Sphingosine kinase 1 promotes tumor progression and confers malignancy phenotypes of colon cancer by regulating the focal adhesion kinase pathway and adhesion molecules

“…Up to now, two mammalian isozymes, SphK1 and SphK2, have been characterized. It is widely accepted that SphK1 resides at the centre of a cell-survival rheostat that balances the cellular levels of pro-apoptotic ceramide with anti-apoptotic S1P (2,3). Evidence also showed that SphK1 enhances cancer cell migration by secretion of S1P in a protein kinase C-α-and ERK1̸2-dependent manner (4).…”

Sphingolipids: A Potential Molecular Approach to Treat Allergic Inflammation

“…Interestingly, the localization of SK-1 and SK-2 differs with SK-1 being predominantly found in the cytoplasm and at the plasma membrane leading to prosurvival effects [61, 62], and SK-2 being predominantly found in the nucleus and at the endoplasmic reticulum (ER) promoting proapoptotic effects [63, 64] (Figure 3). Three splice isoforms of SK-1 have been identified (i.e., SK-1a, SK-1b, and SK-1c) that differ at their N-termini with additional 14 and 86 amino acids in SK-1b and SK-1c, respectively [65].…”