Abstracts (complete list) - Wissenschaft Online

Bernhard Reis, Tanja Scheikl, Norbert Huser, Bernhard Holzmann, Klaus Pfeffer,
Sandra Beer
SLy-an Orphan Adaptor Protein Displaying a Nonredundant
Role in Lymphocyte Development and Activation
Lymphocyte activation by antigen receptor triggering is an essential step in adaptive
immunity which must be tightly regulated to mount an immune response towards a
pathogen and to avoid autoimmune disorders. Major players in this complex network
are adapter proteins containing characteristic SH2 or SH3 domains which are known to
mediate protein protein interactions.
SH3 and SAM domain containing protein expressed in lymphocytes (SLy) is a member
of a distinct family of putative adapter and/or scaffold proteins highly conserved in
mammals. SLy is exclusively expressed in lymphocytes and has been shown to be
phosphorylated specifically upon antigen receptor engagement.
To investigate the physiological functions of SLy, sly-mutant mice expressing a
truncated protein lacking the nuclear localisation signal and the phosphorylation site
(SLYD/D) have been generated by our group. SlyD/D mice exhibit reduced lymphoid
organ sizes, diminished marginal zone B cell numbers and severely impaired antibody
responses against T-dependent and -independent antigens. B and T cell proliferation is
attenuated and T cell cytokine production is severely reduced. In vivo, survival of semiidentical
cardiac allografts was substantially prolonged in Sly1D/D mice. However,
global tyrosine and MAP Kinase phosphorylation, Ca2+ flux and transcription factor
activation are normal. We show that SLy wild-type protein specifically shuttles in
between nucleus and cytoplasm after antigen receptor activation. In contrast, SLymutant
protein shuttling is impaired. The signal transduction pathway leading to the
induced translocation of SLy protein and the role of the phosphorylation status and the
nuclear localisation signal are further dissected.
To further characterize the importance of SLy protein and to determine if the truncated
form acts in a dominant negative way, we recently generated full knockout mice
(SLy-/-). Preliminary data will be presented comparing the related phenotype of SLy-/-
mice and SlyD/D mice, respectively.