An essential role for the MAL protein in targeting Lck to the plasma membrane of human T lymphocytes

Speaker: Li-Shiung Wei                                  Time: 15:10-16:00, Feb.18, 2009

Commentator: Dr. Pin Ling                                     Place:  Room 601

Abstract:

Lck, a member of src family kinases, plays an essential role in T cell receptor (TCR) signaling, through initiating kinase phosphorylation cascade and downstream transcriptional events. Lck is transported to cell surface by an exocytotic pathway and its presence at plasma membrane is required for T cell signaling. The regulation of Lck trafficking, however, is still unclear. MAL is a protein expressed in T cells and polarized epithelial cells. Although the essential role of MAL in epithelial apical transport has been well established, little is known about its function in T cells. In this paper, using a MAL-null T cell line or MAL knockdown experiments, the authors defined that MAL is important for many TCR-triggered molecular events, including polarization of TCR, ZAP-70, PKC-q and MTOC to immunological synapses, activation of ERK, NF-kB and NFAT pathways, and transcription of interleukin-2. Of note, in normal T cells, MAL was associated with Lck and transported together to plasma membrane. Depletion of MAL abrogated Lck expression at cell surface, leading to Lck accumulation in the intracellular compartment. Some defects in MAL-depleted T cells, such as polarization of TCR, ZAP-70 and PKC-q, were corrected by forced expression of plasma membrane-anchored Lck, but complete rescue of molecular polarization to immunological synapses, TCR downstream signaling pathways and IL-2 transcription was achieved only by complementation with MAL. Therefore, MAL is pivotal to TCR-mediated T cell activation, by targeting Lck to plasma membrane and some other mechanisms.

References:

1.      Expression of MAL, an intergral protein component of the machinery for raft-mediated apical transport, in human epithelia. Mónica Marazuela et al., J Histochem Cytochem. 51:665-673. (2003)

2.  Trafficking of an acylated cytosolic protein: Newly synthesized p56 lck travels to the plasma membrane via the exocytic pathway. Marie-José J.E. Bijlmakers and Mark Marsh. J Cell Biol. 145:457-468. (1999)