SAP couples Fyn to SLAM immune receptors

Abstract

SAP (SLAM-associated protein) is a small lymphocyte-specific signalling molecule that is defective or absent in patients with X-linked lymphoproliferative syndrome (XLP). Consistent with its single src homology 2 (SH2) domain architecture and unusually high affinity for SLAM (also called CD150), SAP has been suggested to function by blocking binding of SHP-2 or other SH2-containing signalling proteins to SLAM receptors. Additionally, SAP has recently been shown to be required for recruitment and activation of the Src-family kinase FynT after SLAM ligation. This signalling 'adaptor' function has been difficult to conceptualize, because unlike typical SH2-adaptor proteins, SAP contains only a single SH2 domain and lacks other recognized protein interaction domains or motifs. Here, we show that the SAP SH2 domain binds to the SH3 domain of FynT and directly couples FynT to SLAM. The crystal structure of a ternary SLAM-SAP-Fyn-SH3 complex reveals that SAP binds the FynT SH3 domain through a surface-surface interaction that does not involve canonical SH3 or SH2 binding interactions. The observed mode of binding to the Fyn-SH3 domain is expected to preclude the auto-inhibited conformation of Fyn, thereby promoting activation of the kinase after recruitment. These findings broaden our understanding of the functional repertoire of SH3 and SH2 domains.

SAP Facilitates Recruitment and Activation of LCK at NTB-A Receptors during Restimulation-Induced Cell Death

“…FYN is considered the key Src-family kinase required for SLAM-R signaling, based on its SAP-dependent association with several other SLAM-Rs (13)(14)(15)(16)(17)(18)(19)(20). Although LCK was previously implicated in phosphorylation of both SLAM and CD84 (17,24), no direct association between LCK and a SLAM-R had been detected to date.…”

“…Previous studies either relied on overexpression constructs for biochemical analysis of NTB-A signaling (19) or focused on thymocytes, NK cells, or NK cell lines (13)(14)(15)(16)(17)(18)(19)(20). In the latter case, it is possible that cell type-based differences in the expression of FYN, LCK, SAP, or the SLAM family receptor examined could account for differences in the associations detected.…”

“…Two Srcfamily kinases are primarily involved in initiating TCR signaling: LCK and FYN (12). FYN is the major Src-family kinase shown to mediate signal transduction of SLAM-Rs (including NTB-A) in thymocytes and NK cells (13)(14)(15)(16)(17)(18)(19)(20). To examine the role of both FYN and LCK in RICD, we first used highly selective inhibitors for FYN (SU6656) (21) or LCK [LCK inhibitor I (LCKi)] (22).…”

Increased proliferation of CD8+ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

“…The adaptor SAP binds with high affinity to tyrosine motifs in the cytoplasmic domain of SLAM family immune receptors, including SLAM (CD150), CD244, CD229, SLAMF6, SLAMF7 and CD84, suggesting that SAP functions are important in modulating signals initiated by the SLAM family receptors [5][6][7][8]. It has been well established that SAP is an essential adaptor due to its capacity to recruit FynT to SLAM and p85 of PI3 K to 2B4, respectively [9,10]. SAP is expressed in activated T, NK and NKT cells, as well as in germinal center B cells [11,12], and is indispensable for normal NKT cell development, generation of a proper Th2 response and Ig class switching in humans and mice [13][14][15][16][17][18].…”

X'e Bağli Geçi̇ş Gösteren Lenfoproli̇ferati̇f Sendrom: Kli̇ni̇k, Patogenez Ve Geneti̇kle İlgi̇li̇ Geli̇şmeler

“…AntiSLAM antikorlarıyla uyarıldığında T hücre proliferasyonuna, Th2 hücrelerin Th1 veya Th0 populasyonuna dönüşümüne ve IFNα salınımına neden olur (13,15). Ortamdaki IL-4 düzeyi azalır (13,16,17). Ayrıca sitotoksik CD8+ T hücreleri prolifere olur ve hücresel sitotoksisiteleri artar.…”