Michael Hallek. M.D. University of Cologne (Germany)

THERAPY/ PROGNOSTIC

Targeting Src-family kinases (SFKs) by membrane-permeant peptides

Grant awarded in 2006

Abstract:

The malignant cells in CLL accumulate mostly due to deficiencies in the regulation of cell death. Phosphorylation of tyrosine residues in proteins turns many proteins on and off. It was the first discovered mechanism of signal transduction inside the cell. A family of enzymes, Src-family kinases (SFKs) catalyzes this protein modification step. Since they carry a fatty acid residue, SFKs are usually located close to the inside of the cell membrane and transduce the signals resulting from the stimulation of cell surface receptors that sometimes lack own enzyme activity.

We are going to investigate the influence of B-cell receptor (BCR) stimulation on signaling processes that might determine whether tumor cells survive or die. Another transmembrane receptor CD5, which is always present on CLL cells, modulates BCR signaling. Both BCR and CD5 are known to interact with at least two SFKs, namely Lyn and Lck, respectively. Our goal is to understand and to correct aberrant signaling processes by interrupting protein-protein associations between cell surface receptors and SFKs by means of cell-permeant peptides.

Chains of less than 20 amino acids are chemically synthesized and contain the fatty acid, myristic acid, which enables the molecules to cross membranes. In cell cultures treated with such membrane-permeant lipopeptides we will examine their effects on the phosphorylation status of certain signaling proteins, on the ability of SFKs and receptors to associate with each other and finally on biological phenomena, e.g. cytokine production and frequency of cell death. The sequence and structure of peptides blocking survival pathways is expected to yield valuable information for developing small molecule drugs.