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Modulation of the electrophoretic mobility of the linker for activation of T cells (LAT) by the calcineurin inhibitors CsA and FK506: LAT is a potential substrate for PKC and calcineurin signaling pathways. Cell Signal 2003 Jan;15(1):85-93

Date

10/29/2002

Pubmed ID

12401523

DOI

10.1016/s0898-6568(02)00046-3

Abstract

The linker for activation of T cells (LAT) is essential for T cell activation. Cyclosporin A (CsA) and FK506, inhibitors of T cell proliferation, have been very useful for preventing autoimmune and inflammatory disease and graft rejection. However, both compounds are associated with side effects. We show that TCR ligation in the presence of FK506 or CsA induced rapid modifications in LAT that modulate the electrophoretic mobility of the molecule in SDS-PAGE. Calcineurin, a target for CsA and FK506, dephosphorylated LAT in vitro and restored its electrophoretic mobility. Stimulating T cells with the protein kinase C (PKC) activator PMA induced a shift in the mobility of LAT, whereas inhibitors of PKC blocked the effect of PMA. Thus, manipulating calcineurin or PKC activation alters the electrophoretic mobility of LAT. These results shed light on the molecular actions of CsA and FK506 in T cells and implicate LAT in mediating the drugs' actions.

Author List

Cho CS, Elkahwaji J, Chang Z, Scheunemann TL, Manthei ER, Hamawy MM

Author

Tara L. Petersen MD, MSED Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adaptor Proteins, Signal Transducing
Calcineurin
Calcium
Carrier Proteins
Cells, Cultured
Cyclosporine
Electrophoresis, Polyacrylamide Gel
Enzyme Inhibitors
Humans
Immunosuppressive Agents
Jurkat Cells
Kinetics
Membrane Proteins
Phosphoprotein Phosphatases
Phosphoproteins
Phosphorylation
Protein Kinase C
Receptors, Antigen, T-Cell
Signal Transduction
Sirolimus
T-Lymphocytes
Tacrolimus
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a