Success for the signaling research at the BIOSS cluster of excellence in Freiburg
The distinguished scientific journal Science Signaling picks BIOSS publication for its list of „Signaling Breakthroughs of the Year 2010
To redefine Syk as a dual-specificity kinase self-regulating the signalling output of the B-cell antigen receptor (BCR) marks a first for signalling studies
The work, published by Dr. Simona Infantino, Dr. Beate Heizmann and Prof. Michael Reth from the University of Freiburg and the Max-Planck-Institute of Immunobiology & Epigenetics in the renowned journal PNAS, focuses on the function of the key enzyme Syk, which is currently at the centre of intensive research activity of molecular biologists. The gene encoding Syk is one of the most-frequently mutated genes in human cancer cells. One part of the problem posed by Syk which had been puzzling researchers has been solved by the BIOSS scientists: they were able to detect the double role of the enzyme. Whereas in some tumours Syk appears to play the role of a tumour promoter, it acts more as a tumour suppressor in others. It might be that these different modes of action are linked to the dual activity of the kinase discovered by the BIOSS researchers. Syk is a member of the family of tyrosine kinases and a pivotal signal transducer in cells of our immune system. To redefine Syk as a dual-specificity kinase self-regulating the signalling output of the B-cell antigen receptor (BCR) marks a first for signalling studies.
The work carried out by the Freiburg research team originated from the observation that not only tyrosine residues but also those of serine become phosphorylated at the receptor tails of the BCR during B-cell activation. In this process, tyrosine phosphorylation stimulates B-cell activation whereas serine phosphorylation rather seems to inhibit it. This discovery ushered in a ten-year-long quest of intensive search for the kinase mediating the serine phosphorylation. In this regard, looking for the corresponding kinase to a phosphorylated protein in a cell resembles the search for a needle in a haystack.
In order to tackle the problem, Heizmann et al. used a synthetic biology approach. They employed a method developed at BIOSS for their research: rebuilding a mammalian BCR and its associated elements of signal transduction in the cell of the fruit fly Drosophila. Co-expression of the BCR with various serine/threonine kinases did not lead to any BCR phosphorylation whilst a control experiment with the protein tyrosine kinase Syk not only showed phosphorylation of tyrosine but also phosphorylation of serine residues. “Many of our colleagues remained very sceptical toward these surprising results. It therefore took a while and a lot of controls for us to convince ourselves and our reviewers that Syk really is a dual-specificity kinase that self-regulates the signal output of the B-cell antigen receptor,” explains Beate Heizmann. By now it has become accepted that in B-cell activation Syk initially promotes BCR signal transduction through tyrosine phosphorylation but then inhibits it through serine phosphorylation. It is not yet understood how the kinase switches from one activity to another. Yet this new level of knowledge could already have a significant impact on the understanding and treatment of cancer in humans.
The publication in PNAS was only made possible by the cooperation between the two young female scientists. The close collaboration with Beate Heizmann enabled Simona Infantino to carry out the demanding research in the lab whilst being pregnant and later on being a mother.
Publikation in PNAS:
“Syk is a dual-specificity kinase that self-regulates the signal output from the B-cell antigen receptor”, Beate Heizmann, Michael Reth, Simona Infantino
PNAS, 26 October 2010 Vol. 107, no. 43, p. 18563-18568. DOI: 10.1073/pnas.1009048107
2010: Signaling Breakthroughs of the Year
Sci. Signal., 4 January 2011. Vol. 4, Issue 154, p. eg1. DOI: 10.1126/scisignal.2001770