Importance and mechanism of 'switch' function of SAP family adapters.
The signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) family of adapters includes SAP, Ewing's sarcoma-associated transcript-2 (EAT-2), and EAT-2-related transducer (ERT). These Src homology-2 (SH2) domain-only molecules play critical roles in immune regulation. The prototype of the SAP family, SAP, is mutated in X-linked lymphoproliferative disease in humans. Moreover, genetically engineered mice lacking one or more SAP family members have defects in multiple immune cell types including T cells, natural killer (NK) cells, NKT cells, and B cells. Accumulating data show that SAP family adapters regulate immunity by influencing the functions of SLAM family receptors, through two distinct but cooperative mechanisms. First, SAP family adapters couple SLAM family receptors to active biochemical signals, which promote immune cell functions. Second, SAP family adapters interfere with the intrinsic ability of SLAM family receptors to trigger inhibitory signals, which could be mediated via molecules such as SH2 domain-containing 5'-inositol phosphatase-1. The latter effect of SAP family adapters does not seem to be because of direct blocking of inhibitory effector binding to SLAM family receptors. Rather, it appears to implicate alternative mechanisms such as functional competition, trans-regulation, or steric hindrance. In the absence of SAP family adapters, the inhibitory signals mediated by SLAM family receptors suppress critical activating receptors, explaining in part the pronounced phenotypes seen in SAP family adapter-deficient humans and mice. Thus, SAP family adapters are molecular switches that regulate immunity as a result of their capacity to control the type of signals and functions emanating from SLAM family receptors.
Veillette
André
A
Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec, Canada. veillea@ircm.qc.ca
Dong
Zhongjun
Z
Pérez-Quintero
Luis-Alberto
LA
Zhong
Ming-Chao
MC
Cruz-Munoz
Mario-Ernesto
ME
D000494:Allosteric Regulation; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D001667:Binding, Competitive; D006801:Humans; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D055503:Protein Multimerization / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D018909:src Homology Domains / Q000276:immunology
D015703:Antigens, CD; D011956:Receptors, Cell Surface; C103572:SH2D1B protein, human; D014157:Transcription Factors; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D048055:Mitogen-Activated Protein Kinase 8