Alexander Tarakhovsky

Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases.

The Src family of protein tyrosine kinases (Src-PTKs) is important in the regulation of growth and differentiation of eukaryotic cells. The activity of Src-PTKs in cells of different types is negatively controlled by Csk, which specifically phosphorylates a conserved regulatory tyrosine residue at the carboxy-terminal tail of the Src-PTKs. Csk is mainly cytoplasmic and Src-PTKs are predominantly membrane-associated. This raises a question about the mechanism of interaction between these enzymes. Here we present Cbp—a transmembrane phosphoprotein that is ubiquitously expressed and binds specifically to the SH2 domain of Csk. Cbp is involved in the membrane localization of Csk and in the Csk-mediated inhibition of c-Src. In the plasma membrane Cbp is exclusively localized in the GM1 ganglioside-enriched detergent-insoluble membrane domain, which is important in receptor-mediated signalling. These findings reveal Cbp as a new component of the regulatory mechanism controlling the activity of membrane-associated Src-PTKs.

CD5-Mediated Negative Regulation of Antigen Receptor-Induced Growth Signals in B-1 B Cells

A subset of B lymphocytes present primarily in the peritoneal and pleural cavities is defined by the expression of CD5 and is elevated in autoimmune diseases. Upon signaling through membrane immunoglobulin M (mIgM), splenic B lymphocytes (B-2) proliferate, whereas peritoneal B cells (B-1) undergo apoptosis. However, in CD5-deficient mice, B-1 cells responded to mIgM crosslinking by developing a resistance to apoptosis and entering the cell cycle. In wild-type B-1 cells, prevention of association between CD5 and mIgM rescued their growth response to mIgM crosslinking. Thus the B cell receptor-mediated signaling is negatively regulated by CD5 in normal B-1 cells.

The B-cell-specific Src-family kinase Blk is dispensable for B-cell development and activation.

ABSTRACT The B-cell lymphocyte kinase (Blk) is a src-family protein tyrosine kinase specifically expressed in B-lineage cells of mice. The early onset of Blk expression during B-cell development in the bone marrow and the high expression levels of Blk in mature B cells suggest a possible important role of Blk in B-cell physiology. To study the in vivo function of Blk, mice homozygous for the targeted disruption of the blk gene were generated. In homozygous mutant mice, neither blk mRNA nor Blk protein is expressed. Despite the absence of Blk, the development, in vitro activation, and humoral immune responses of B cells to T-cell-dependent and -independent antigens are unaltered. These data are consistent with functional redundancy of Blk in B-cell development and immune responses.

B-1 cells: orthodox or conformist?

B-1 cells differ from conventional peripheral B cells (B-2) by anatomical location, surface marker expression, antibody repertoire and growth properties. The lineage hypothesis of B-1 cell development attributes the properties of B-1 cells to their unique origin. The induced differentiation hypothesis suggests the surface-immunoglobulin-driven development of B-1 cells from common B-1/B-2 cell progenitors. In both models self-antigen-induced signalling plays the central role in positive selection of B-1 cells. The ability of B-1 cells to be positively selected by self-antigens raises questions about the mechanism of this phenomenon.

An influence of CD5 on the selection of CD4‐lineage T cells

Combining CD5‐null, MHC‐deficient and lineage‐specific reporter animals, we have investigated the influence of CD5 on positive selection and the choice of CD4‐ versus CD8‐lineage commitment on broad populations of thymocytes. CD5 has no obvious quantitative effect in wild‐type mice. In mice lacking MHC class II molecules, however, increased numbers of transitional, class I‐selected CD4+ CD8int CD3hi cells were positively selected in the absence of CD5. Importantly, they were committed to the CD4 lineage. Our results indicate that CD5 negatively regulates the differentiation of CD4‐committed cells in suboptimal conditions, thus perhaps serving to tighten the correlation between restriction of the TCR and lineage choice.

Xid and Xid-like immunodeficiencies from a signaling point of view

The analysis of Btk-associated molecules and ligand-induced Btk phosphorylation has suggested the existence of a complexed Btk-associated signaling network involved in the activation of B lymphocytes and mast cells. Recent gene targeting experiments have revealed protein kinase C betaI/II (PKCbetaI/II) as a critical component of the Btk-dependent signaling chain and have highlighted a potential role for the Btk-PKCbetaI/II interaction in the amplification of B cell receptor mediated signaling.