A specific type of membrane microdomains is involved in the maintenance and translocation of kinase active Lck to lipid rafts

0377765 - ÚMG 2013 RIV NL eng J - Článek v odborném periodiku
Ballek, Ondřej - Broučková, Adéla - Manning, Jasper - Filipp, Dominik
A specific type of membrane microdomains is involved in the maintenance and translocation of kinase active Lck to lipid rafts.
Immunology Letters. Roč. 142, 1-2 (2012), s. 64-74. ISSN 0165-2478. E-ISSN 1879-0542
Grant CEP: GA ČR GA310/09/2084
Výzkumný záměr: CEZ:AV0Z50520514
Klíčová slova: pY394Lck * T-cell proximal signaling * membrane microdomains
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 2.337, rok: 2012

Lck is the principal signal-generating tyrosine kinase of the T cell activation mechanism. We have previously demonstrated that induced Lck activation outside of lipid rafts (LR) results in the rapid translocation of a fraction of Lck to LR. While this translocation predicates the subsequent production of IL-2, the mechanism underpinning this process is unknown. Here, we describe the main attributes of this translocating pool of Lck. Using fractionation of Brij58 lysates, derived from primary naive non-activated CD4(+) T cells, we show that a significant portion of Lck is associated with high molecular weight complexes representing a special type of detergent-resistant membranes (DRMs) of relatively high density and sensitivity to laurylmaltoside, thus called heavy DRMs. TcR/CD4 coaggregation-mediated activation resulted in the redistribution of more than 50% of heavy DRM-associated Lck to LR in a microtubular network-dependent fashion. Remarkably, in non-activated CD4(+) T-cells, only heavy DRM-associated Lck is phosphorylated on its activatory tyrosine 394 and this pool of Lck is found to be membrane confined with CD45 phosphatase. These data are the first to illustrate a lipid microdomain-based mechanism concentrating the preactivated pool of cellular Lck and supporting its high stoichiometry of colocalization with CD45 in CD4(+) T cells. They also provide a new structural framework to assess the mechanism underpinning the compartmentalization of critical signaling elements and regulation of spatio-temporal delivery of Lck function during the T cell proximal signaling.
Trvalý link: http://hdl.handle.net/11104/0216415