TY - JOUR
T1 - The Adaptor SAP Controls NK Cell Activation by Regulating the Enzymes Vav-1 and SHIP-1 and by Enhancing Conjugates with Target Cells
AU - Dong, Zhongjun
AU - Davidson, Dominique
AU - Pérez-Quintero, Luis Alberto
AU - Kurosaki, Tomohiro
AU - Swat, Wojciech
AU - Veillette, André
N1 - Funding Information:
We thank S. Latour and M. Cruz for discussions, N. Wu for help with quantitation, and L. Yin for sharing the SAP-deficient mouse. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) and the Canadian Cancer Society Research Institute to A.V. Z.D. was recipient of a fellowship from CIHR, and A.V. holds the Canada Research Chair in Signaling in the Immune System and was an International Scholar of the Howard Hughes Medical Institute.
PY - 2012/6/29
Y1 - 2012/6/29
N2 - The adaptor SAP, mutated in X-linked lymphoproliferative disease, has critical roles in multiple immune cell types. Among these, SAP is essential for the ability of natural killer (NK) cells to eliminate abnormal hematopoietic cells. Herein, we elucidated the molecular and cellular bases of this activity. SAP enhanced NK cell responsiveness by a dual molecular mechanism. It coupled SLAM family receptors to the kinase Fyn, which triggered the exchange factor Vav-1 and augmented NK cell activation. SAP also prevented the inhibitory function of SLAM family receptors. This effect was Fyn independent and correlated with uncoupling of SLAM family receptors from the lipid phosphatase SHIP-1. Both mechanisms cooperated to enable conjugate formation with target cells and to stimulate cytotoxicity and cytokine secretion by NK cells. These data showed that SAP secures NK cell activation by a dichotomous molecular mechanism, which is required for conjugate formation. These findings may have implications for the role of SAP in other immune cell types.
AB - The adaptor SAP, mutated in X-linked lymphoproliferative disease, has critical roles in multiple immune cell types. Among these, SAP is essential for the ability of natural killer (NK) cells to eliminate abnormal hematopoietic cells. Herein, we elucidated the molecular and cellular bases of this activity. SAP enhanced NK cell responsiveness by a dual molecular mechanism. It coupled SLAM family receptors to the kinase Fyn, which triggered the exchange factor Vav-1 and augmented NK cell activation. SAP also prevented the inhibitory function of SLAM family receptors. This effect was Fyn independent and correlated with uncoupling of SLAM family receptors from the lipid phosphatase SHIP-1. Both mechanisms cooperated to enable conjugate formation with target cells and to stimulate cytotoxicity and cytokine secretion by NK cells. These data showed that SAP secures NK cell activation by a dichotomous molecular mechanism, which is required for conjugate formation. These findings may have implications for the role of SAP in other immune cell types.
UR - http://www.scopus.com/inward/record.url?scp=84862976954&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2012.03.023
DO - 10.1016/j.immuni.2012.03.023
M3 - Article
C2 - 22683124
AN - SCOPUS:84862976954
VL - 36
SP - 974
EP - 985
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 6
ER -