„Signaling is very complex“, Edmond Fischer emphasizes at the beginning of this talk, his fourth one at the Lindau Nobel Laureate Meetings. Yet this complexity appears less daunting and more challenging when one listens to Fischer who is one of the pioneers of signaling research and at the age of 83 still an engaging and prolific speaker. Together with Edwin Krebs he had discovered the mechanism of reversible protein phosphorylation, which turned out to be the most prevalent switch of intracellular communication. In this presentation, however, he only briefly mentions his own achievement and turns to the wider field of signal integration within cells. Even if the unraveling of the human genome was an „achievement of enormous proportion“, the knowledge of the genome is not nearly sufficient to explain and understand cellular signaling. „The cell in a body is exposed to a multitude of signals that it has to integrate into a coherent response“, he says. „The pathways have to speak to another – this is a subject that belongs to the field of proteomics.“ Focussing on signal transduction via enzyme-coupled receptors, Fischer summarizes current knowledge on how extracellular signals are relayed into the cell, and then turns to a detailed description of interaction domains, which allow signaling proteins to assemble to signaling complexes that consequently trigger downstream cascades. „Communication is practical mechanical: Proteins interlock with one another, comparable to lego“, Fischer says. Vividly he introduces form and function of interaction domains such as SH2, PH, and PDZ to his audience. It is typical for Fischer that he does not get lost in details but keeps the big questions at the horizon in mind. „How does the cell select among all it can do?“ Doesn’t its situation resemble that of a car driver who finds himself in a roundabout that can send him to many different directions? How can a cell, faced with a plethora of signals, choose the right combinatorial type of response? „We know several important pathways, their structures and elements“, Fischer concludes. „But these molecules are only the words that the cell brings about to modify its behaviour. We know some of these words, even pieces of sentences, but we do not know the language the cell uses to synchronize the signals.“Joachim Pietzsch

The types of reaction a cell uses to transduce an external signal into a particular response will be discussed. The subject belongs to the field of proteomics as opposed to genomics. Some characteristics of both will be contrasted, emphasizing that the proteome that remains constantly in a state of flux represents a far more complex and dynamic entity than the genome.

The main focus of the talk will be on signalling by tyrosine phosphorylation which has been directly implicated in the regulation of cell growth, differentiation and transformation. External signals coming in the form of mitogenic hormones and growth factors act on transmembrane receptors that are themselves tyrosine kinases; these, in turn, transduce they signals with the help of a variety of adapter or docking proteins that interact with one another through a diversity of binding domains, thereby initiating different signalling pathways. Some of the properties of these modules will be detailed. The src-homology 2 (SH2) domain, in addition to allowing adapter or linker proteins to bind to activated receptors, can also serve as an internal conformational switch to regulate the activity of various enzymes. The PH domain recruits protein to the membrane while the PDZ domain which is usually found in multiple copies within a protein serves mainly to cluster ion-channels and receptors on the membrane, and bridge them to the cytoskeleton.

Transmembrane protein tyrosine phosphatases which catalyze the reverse reaction also have a modular structure, often containing immunoglobulin-like and/or fibronectin type III repeats. Surprisingly and contrary to the tyrosine kinase growth factor receptors that respond mainly to circulating ligands, the tyrosine phosphatase receptors display all the hallmarks of cell adhesion molecules. This would suggest that they are involved in, or regulated by, cell-cell or cell-matrix interaction, with the exciting possibility that they might be directly implicated in contact inhibition. Some of the problems that confront us in the field of cell signalling and remain to be solved will be summarized.