Achievements

We have cloned the SH2D2A gene encoding T cell specific adapter protein (Spurkland et al, JBC, 1998), and found that it modulates early signal transduction events in T cells, possibly through direct interaction with the crucial tyrosine kinase Lck (Sundvold-Gjerstad et al, Eur. J. Immunol. 2005).

We have proposed that through multivalent interactions with the T cell specific Src family tyrosine kinase Lck, TSAd diverts Lck from phosphorylating other substrates, thus modulating its functional activity through substrate competition (Granum et al, JBC, 2008). Since TSAd is not expressed in resting T cells, but is rapidly induced upon activation of the T cell (Dai et al, J. Immunol., 2004, Kolltveit et al, Molecular Immunol. 2008), it can be viewed as an induced heterodimerisation partner for Lck.

TSAd also interacts with the T cell specific Tec family tyrosine kinase Itk. The trimolecular complex of TSAd, Lck and Itk promotes Lck mediated phosphorylation of Itk and chemokine induced migration of T cells (Berge et al, PlosOne, 2010). TSAd also promote phosphorylation of Lck Tyr192 by Itk, thus shifting the specificity of Lck (Granum et al. Science signaling 2014).

Mice engineered to express T cell receptors specific for a myeoloma antigen, display increased resistance to the myeloma in the absence of TSAd (Berge et al, PlosOne 2012).

In collaboration with professor Lena Claesson-Welsh, Uppsala, we have found that TSAd is also expressed in endothelial cells, where upon stimulation with VEGF it is recruited via its SH2 domain to VEGF receptor 2 (VEGFR2) and thus regulate stress induced F-actin formation and angiogenesis (Matsumoto et al, Embo J, 2005). TSAd also regulates permeability of endothelial cells upon VEGF stimulation (Sun et al, JEM, 2012).

Published Feb. 22, 2011 6:55 PM - Last modified Jan. 11, 2021 6:33 PM