Abstract
The alpha(1,3)-fucosyltransferase FucT-VII is essential for the biosynthesis of selectin ligands, but the signaling pathways mediating FucT-VII induction in T cells and other lymphocytes are poorly understood. We have shown previously that sustained activation of Ras in Jurkat T cells induces FucT-VII transcription, which requires the Raf-MEK-ERK pathway. In this study we report that FucT-VII induction is specific to the H-Ras isoform. Jurkat T cells retrovirally transduced with constitutively active H-Ras but not N- or K-Ras up-regulated expression of FucT-VII. Pharmacological inhibition studies also revealed that phosphoinositide 3-kinase (PI3K) activity is required for H-Ras-mediated FucT-VII induction. However, the ability of H-Ras to selectively induce FucT-VII is not a function of the inability of the N- or K-Ras isoforms to activate Raf or PI3K pathways. The use of effector-loop domain mutants of H-Ras, which are impaired for their ability to interact selectively with individual effectors alone or in combination with active Raf, indicated that induction of FucT-VII requires the concomitant activation of at least three signaling pathways. These studies show that H-Ras mediates FucT-VII induction in Jurkat T cells via the activation of the Raf, PI3K, and a distinct, H-Ras-specific effector signaling pathway.
Highlights
T cells, once activated after antigen encounter, migrate to extravascular compartments via a cascade-like process involving capture, rolling on the endothelial surface, arrest, and eventually transmigration [1]
Pharmacological inhibition studies revealed that phosphoinositide 3-kinase (PI3K) activity is required for H-Ras-mediated FucT-VII induction
The ␣(1,3)-fucosyltransferase FucT-VII,1 is essential for the biosynthesis of all selectin ligands in all cells in which it has been examined, including monocytes, neutrophils, and other myeloid cells as well as the biosynthesis of Eand P-selectin ligands on activated T cells [7, 8]
Summary
FucT-VII, ␣(1,3)-fucosyltransferase VII; TCR, T cell receptor; PI3K, phosphoinositide 3-kinase, RalGDS, RalGDP dissociation stimulators; ERK, extracellular signal-regulated kinase; GFP, green fluorescent protein; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; MSCV, murine stem cell virus; IRES, internal ribosome entry site; FACS, fluorescence-activated cell sorter; PTEN, phosphatase and tensin homologue. We demonstrate that PI3K, an important Ras downstream effector, is required for H-Ras-induced FucT-VII expression and that H-Ras mediates FucT-VII induction through the concomitant activation of at least three signaling pathways
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