Chinese Bulletin of Life Sciences. NTAL/LAB: immuno-regulatory role in lymphocyte development and function. WANG Ying

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1 Chinese Bulletin of Life Sciences Vol. 17, No. 3 Jun., (2005) NTAL/LAB NTAL/LAB B FcγRI FcεRI NTAL/LAB NTAL/LAB ; NTAL/LAB; Q25; Q51 A NTAL/LAB: immuno-regulatory role in lymphocyte development and function WANG Ying (Shanghai Institute of Immunology, Shanghai Second Medical University, Shanghai , China) Abstract: Adaptor proteins mediate protein-protein and protein-lipid interactions. They play a pivotal role in organization and assembly of immunoreceptor-initiated signaling during the development and activation of lymphocytes. Upon phosphorylation by proper kinases, they can recruit certain proteins and act as molecular scaffolds through which multiprotein signaling complexes are assembled via signaling motifs (e.g. Src homology 2 (SH2)-, Src homology 3 (SH3)-, pleckstrin homology (PH)-domains). The recently identified transmembrane adaptor protein NTAL (non-t cell activation linker)/lab (linker for activation of B cells) facilitates our understanding of how this protein regulates signaling within activation and differentiation of lymphocytes. Key words: adaptor proteins; NTAL/LAB; lymphopoiesis and function 1 (adaptor proteins) ( SH2 PH ) (1969 )

2 252 (scaffolds) T B T LAT [1] SLP-76 [2] T T (DN3) T T TCR TCR B BLNK/SLP-65 B B [3] (transmembrane adaptor proteins) (cytosolic adaptor proteins) LAT PAG [4] LIME [5] NTAL/LAB TCRξ DAP12 LAX [6] TRIM [7] SIT [8] (glycosphinolipid-enriched microdomains, GEMs) [9] (proximity) [10] 2 NTAL Václav Hoejí1rs [11] Zhang [12] NTAL (non-t cell activation linker)/lab (linker for activation of B cells) GeneBank wbscr5 243 ( 203 ) 7 ( 5 ) N (6 ) CXXC GEMs Grb2 Gads YXN ( Y 95 Y 118 Y 136 Y 193 Y 233 ) B NK T B ( Raji ) ( THP-1 K562 ) NK (YT) T (Jurkat) (Hela) B FcγRI FcεRI NTAL/LAB Lck Syk lyn ZAP-70 NTAL Grb2 SOS1 C-Cbl Gads Ras-MAPK PLC-γ PLCγ-PKC-Ca 2+ NTAL

3 NTAL/LAB 253 (T B NK ) NTAL NTAL 3 NTAL NTAL [13~14] I IgE FcεRI IgE FcεRI FcεRI NATL NTAL FcεRI NTAL Lyn Grb2 SHP-2 SHP-2 SH2 FcεRI NTAL SHP-2 NTAL LAT NTAL LAT FcεRI 4 NTAL T NTAL T NTAL T Th2 Th2 LAT Y136F Th2 NTAL B NTAL Grb2 NTAL LAT T NTAL LAT T Jurkat Jurkat TCR Erk NTAL LAT RAG T T [12] ; NTAL LAT LAT Y136F [15~16] T TCR T Th2 [17] LAT 136 PLC-γ1 [18] NTAL LAT Y136F PLC-γ1 NTAL LAT TCR NTAL LAT LAT NTAL CXXC TCR Grb2 Grb2 MAPK T 5 NTAL B NTAL B NTAL - LAT TCR TCR SLP-76 B SLP-65 SLP-76 T LAT TCR ZAP-70 TCR B LAT BCR NTAL B T NTAL LAT B BCR NTAL B BCR RAS-MAPK NTAL BCR NTAL B B B NTAL [19] BLNK/SLP-65 N BCR NTAL B

4 254 NTAL IgM B T NTAL PLC-γ2 NTAL PLC-γ2 PLC-γ2 NTAL NTAL NTAL B NTAL B B DT40 Grb2 SHP-1 BCR NTAL Grb2 [20] B BCR 6 NTAL NK NK NTAL NK NTAL NK NTAL NK [21] 7 NTAL LAT NTAL LAT LAT NTAL FcεRI Lck ZAP-70 LAT NTAL NTAL LAT LAT NTAL FcεRI LAT FcεRI LAT NTAL LAT PLC-γ SOS1 MAPK NTAL NTAL Grb2 SHP-2 NTAL LAT FcεRI NTAL FcεRI NTAL LAT FcεRI LAT NTAL LAT LAT Grb2/SOS1-RAS-MAPK NTAL Grb2 NTAL LAT PLC-γ PLC-γ PIP 2 DAG IP 3 DAG PKC RAS-MAPK IP 3 NF-AT Grb2 MAPK NTAL LAT T NTAL LAT LAT LAT NTAL PLCγ PLC-γ PLC-γ LAT LAT LAT-PLCγ NTAL LAT Grb2-RAS- MAPK NTAL Grb2-SHP-1(SHP-2) NTAL LAT

5 NTAL/LAB 255 NTAL Grb2-MAPK PLC-γ NTAL LAT LAT NTAL NK LAT NTAL NK NK NK NK LAT NTAL NK 8 NTAL FcεRI LAT LAT T NTAL LAT LAT TCR FcεRI NTAL NTAL B NTAL B BCR NTAL B B NTAL B [1] Zhang W, Sloan-Lancaster J, Kitchen J, et al. LAT, the ZAP- 70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell, 1998, l 92: 83~92 [2] Meyers E E, Sigmund C D, Freedman B D, et al. Differential requirement for SLP-76 domains in T cell development and function. Immunity, 2001, 15: 1011~1026 [3] Fu C, Turck C W, Kurosaki T, et al. BLNK: a central linker protein in B cell activation. Immunity, 1998, 9: 93~103 [4] Brdicka T, Pavlistova D, Leo A, et al. Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation. J Exp Med, 2000, 191: 1591~1604 [5] Bridickova N, Brdicka T, Angelisova P, et al. LIME: a new membrane raft-associated adaptor protein involved in CD4 and CD8 coreceptor signaling. J Exp Med, 2003, 198: 1453~1462 [6] Zhu M, Janssen E, Leung K, et al. Molecular cloning of a movel gene encoding a membrance-associated adaptor protein (LAX) in lymphocyte signaling. J Biol Chem, 2002, 277: 46151~46158 [7] Bruyns E, Marie-Cardine A, Kirchgessner H, et al. T cell receptor (TCR) interacting molecule (TRIM), a novel disulfide-linked dimer associated with the TCR-CD3-δ complex, recruits intracellular signaling proteins to the plasma membrane. J Exp Med, 1998, 188: 561~575 [8] Marie-Cardine A, Kirchgessner H, Bruyns E, et al. SHP2- interacting transmembrane adaptor protein (SIT): a novel disulfide-linked dimer regulating human T cell activation. J Exp Med, 1999, 189: 1181~1194 [9] Simons K, Ikonen E. Functional rafts in cell membranes. Nature, 1997, 387: 569~572 [10] Horejsi V. Transmembrane adaptor proteins in membrane microdomains: important regulators of immunoreceptor signaling. Immunol Lett, 2004, 92(1-2): 43~49 [11] Brdicka T, Imrich M, Angelisova P, et al. Non-T cell activation linker (NTAL): a transmembrane adaptor protein involved in immunoreceptor signaling. J Exp Med, 2002, 196: 1617~1626 [12] Janssen E, Zhu M, Zhang W, et al. LAB: A new membraneassociated adaptor molecule in B cell activation. Nat Immunol, 2003, 4: 117~123 [13] Volna P, Lebduska P, Draberova L, et al. Negative regulation of mast cell signaling and function by the adaptor LAB/ NTAL. J Exp Med, 2004, 200: 1001~1013 [14] Zhu M, Liu Y, Koonpaew S, et al. Positive and negative regulation of FcεRI-mediated signaling by the adaptor protein LAB/NTAL. J Exp Med, 2004, 200: 991~1000 [15] Aguado E, Richelme S, Nunez-Cruz S, et al. Induction of T helper type 2 immunity by a point mutation in the LAT adaptor. Science, 2002, 296: 2036~2040 [16] Sommers S L, Park C S, Lee J, et al. A LAT mutation that inhibits T cell development yet induces lymphoproliferation. Science, 2002, 296: 2040~2044 [17] Janssen E, Zhu M, Craven B, et al. Linker for activation of B cells: a functional equivalent of a mutant linker for activation of T cells deficient in phospholipase C-gamma1 binding. J Immunol, 2004, 172: 6810~6819 [18] Zhang W, Trible R P, Zhu M, et al. Association of Grb2, Gads, and phospholipase C-γ 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell angigen receptor-mediated signaling. J Biol Chem, 2000, 275(30): 23355~23361 [19] Wang Y, Horvath O, Hamm-Baarke A, et al. Single and combined deletions of the NTAL/LAB and LAT adaptors minimally affect B-cell development and function. Mol Cell Biol, 2005, 25(11) : 4455~4465 [20] Stork B, Engelke M, Frey J, et al. Grb2 and the non-t cell activation linker NTAL constitute a Ca(2+)-regulating signal circuit in B lymphocytes. Immunity, 2004, 21:681~691 [21] Chiesa S, Mingueneau M, Fuseri N, et al. Multiplicity and plasticity of Natural Killer cell signaling pathways ( in submission)

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