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Non–T Cell Activation Linker (NTAL) : A Transmembrane Adaptor Protein Involved in Immunoreceptor Signaling

Tomá Brdika¹, Martin Imrich¹, Pavla Angelisová¹, Nadda Brdiková¹, Ondrej Horváth¹, Jií pika¹, Ivan Hilgert¹, Petra Lusková¹, Petr Dráber¹, Petr Novák², Niklas Engels³, Jürgen Wienands³, Luca Simeoni⁴, Jan Österreicher⁵, Enrique Aguado⁶, Marie Malissen⁶, Burkhart Schraven⁴ and Václav Hoejí¹

¹ Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeská 1083, 142 20 Prague 4, Czech Republic
² Institute of Microbiology, Academy of Sciences of the Czech Republic, Vídeská 1083, 142 20 Prague 4, Czech Republic
³ Department of Biochemistry and Molecular Immunology, University of Bielefeld, Universitätsstrasse 25, Bielefeld D-33615, Germany
⁴ Institute for Immunology, Otto-von-Guericke-University, Leipziger Strasse 26, 39120 Magdeburg, Germany
⁵ Department of Radiobiology and Immunology, Purkyn Military Medical Academy, Tebeská 1575, 500 01 Hradec Králové, Czech Republic
⁶ Centre d'Immunologie de Marseille-Luminy, INSERM-CNRS-Univ. Med., Parc Scientifique de Luminy, 13288 Marseille Cedex 9, France

Address correspondence to Václav Hoejí, Institute of Molecular Genetics AS CR, Vídeská 1083, 142 20 Praha 4, Czech Republic. Phone: 420-2-41729908; Fax: 420-2-44472282; E-mail: horejsi{at}biomed.cas.cz; or Burkhart Schraven, Institute for Immunology, Otto-von-Guericke-University, Leipziger Strasse 26, 39120 Magdeburg, Germany. Phone: 0391-67-15800; Fax: 0391-67-15852; E-mail: burkhart.schraven{at}medizin.uni-magdeburg.de

A key molecule necessary for activation of T lymphocytes through their antigen-specific T cell receptor (TCR) is the transmembrane adaptor protein LAT (linker for activation of T cells). Upon TCR engagement, LAT becomes rapidly tyrosine phosphorylated and then serves as a scaffold organizing a multicomponent complex that is indispensable for induction of further downstream steps of the signaling cascade. Here we describe the identification and preliminary characterization of a novel transmembrane adaptor protein that is structurally and evolutionarily related to LAT and is expressed in B lymphocytes, natural killer (NK) cells, monocytes, and mast cells but not in resting T lymphocytes. This novel transmembrane adaptor protein, termed NTAL (non–T cell activation linker) is the product of a previously identified WBSCR5 gene of so far unknown function. NTAL becomes rapidly tyrosine-phosphorylated upon cross-linking of the B cell receptor (BCR) or of high-affinity Fc- and Fc-receptors of myeloid cells and then associates with the cytoplasmic signaling molecules Grb2, Sos1, Gab1, and c-Cbl. NTAL expressed in the LAT-deficient T cell line J.CaM2.5 becomes tyrosine phosphorylated and rescues activation of Erk1/2 and minimal transient elevation of cytoplasmic calcium level upon TCR/CD3 cross-linking. Thus, NTAL appears to be a structural and possibly also functional homologue of LAT in non–T cells.

Key Words: lipid rafts • membrane microdomains • antigen receptors • Fc gamma receptor • Fc epsilon receptor

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