TY - JOUR
T1 - A balance between positive and negative signals in cytotoxic lymphocytes regulates the polarization of lipid rafts during the development of cell- mediated killing
AU - Lou, Zhenkun
AU - Jevremovic, Dragan
AU - Billadeau, Daniel D.
AU - Leibson, Paul J.
PY - 2000/1/17
Y1 - 2000/1/17
N2 - Plasma membrane microdomains containing sphingolipids and cholesterol (lipid rafts) are enriched in signaling molecules. The cross-linking of certain types of cell surface receptors initiates the redistribution of these lipid rafts, resulting in the formation of signaling complexes. However, little is known about the regulation of the initial raft redistribution and whether negative regulatory signaling pathways target this phase of cellular activation. We used natural killer (NK) cells as a model to investigate the regulation of raft redistribution, as both positive and negative signals have been implicated in the development of their cellular function. Here we show that after NK cells form conjugates with sensitive tumor cells, rafts become polarized to the site of target recognition. This redistribution of lipid rafts requires the activation of both Src and Syk family protein tyrosine kinases. In contrast, engagement of major histocompatibility complex (MHC)- recognizing killer cell inhibitory receptors (KIRs) on NK cells by resistant, MHC-bearing tumor targets blocks raft redistribution. This inhibition is dependent on the catalytic activity of KIR-associated SHP-1, a Src homology 2 (SH2) domain containing tyrosine phosphatase. These results suggest that the influence of integrated positive and negative signals on raft redistribution critically influences the development of cell-mediated cytotoxicity.
AB - Plasma membrane microdomains containing sphingolipids and cholesterol (lipid rafts) are enriched in signaling molecules. The cross-linking of certain types of cell surface receptors initiates the redistribution of these lipid rafts, resulting in the formation of signaling complexes. However, little is known about the regulation of the initial raft redistribution and whether negative regulatory signaling pathways target this phase of cellular activation. We used natural killer (NK) cells as a model to investigate the regulation of raft redistribution, as both positive and negative signals have been implicated in the development of their cellular function. Here we show that after NK cells form conjugates with sensitive tumor cells, rafts become polarized to the site of target recognition. This redistribution of lipid rafts requires the activation of both Src and Syk family protein tyrosine kinases. In contrast, engagement of major histocompatibility complex (MHC)- recognizing killer cell inhibitory receptors (KIRs) on NK cells by resistant, MHC-bearing tumor targets blocks raft redistribution. This inhibition is dependent on the catalytic activity of KIR-associated SHP-1, a Src homology 2 (SH2) domain containing tyrosine phosphatase. These results suggest that the influence of integrated positive and negative signals on raft redistribution critically influences the development of cell-mediated cytotoxicity.
KW - Cytotoxicity, immunologic
KW - Natural killer cell
KW - Signal transduction
KW - Tyrosine kinase
KW - Tyrosine phosphatase
UR - http://www.scopus.com/inward/record.url?scp=0034677175&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034677175&partnerID=8YFLogxK
U2 - 10.1084/jem.191.2.347
DO - 10.1084/jem.191.2.347
M3 - Article
C2 - 10637278
AN - SCOPUS:0034677175
SN - 0022-1007
VL - 191
SP - 347
EP - 354
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 2
ER -