Research Report 2010 - MDC

Signaling Pathways, Cell Biology, and CancerStructure of the GroupClaus ScheidereitGroup LeaderProf. Dr. Claus ScheidereitScientistsDr. Annette AhlersDr. Michael HinzDr. Eva KärgelDr. Giulietta RoelDr. Ruth Schmidt-UllrichDr. Buket YilmazSignal Transduction in Tumor CellsThe major interest of our laboratory is the regulation of gene expression by cellular signaltransduction processes. ”Nuclear factor kappaB” (NF-κB) denotes a family of transcriptionfactors whose activities are controlled by inhibitory IκB proteins and IκB kinases (IKK). NF-κB/IKK signaling cascades have wide physiological and medical relevance. Major efforts are todecipher the mechanisms and structures that underlie gene regulation by IKK and NF-κB, thecrosstalk with other gene regulatory systems and to dissect both, the role in development andin the pathogenesis of diseases.Molecules and mechanisms that control IKK andNF-κB activityMost if not all cell types of the body utilize NF-κB transcriptionfactors to regulate under various conditionsthe expression of numerous genes. These encodecytokines, surface receptors, adhesion molecules, transcriptionfactors and other functional classes of proteins.Biological processes which involve NF-κB activationinclude the innate and adaptive immune responses,inflammation, cellular reaction to environmentalstress as well as selective aspects of early embryonicdevelopment. In non-stimulated cells, NF-κB is associatedwith IκB molecules, which inhibit nuclear translocationand DNA binding activity of NF-κB. Cellular exposureto a variety of agents or conditions, includingmicrobial pathogens, cytokines, mitogens, genotoxicstress or morphogens triggers the activation of an IκBkinase (IKK) complex, which consists of catalytic (IKKα,IKKβ) and regulatory (IKKγ/NEMO) components. Thiscomplex phosphorylates IκB molecules, resulting intheir ubiquitination by βTrCP/SCF ubiquitin ligases andproteasomal destruction, followed by liberation ofactive NF-κB.In mammals, the NF-κB family comprises five relatedmembers, p50, p52, p65, c-Rel and RelB. These proteinsform distinct hetero- and homodimers and bind toinhibitory cytoplasmic IκB molecules, IκB α,β or ε, or tothe nuclear IκB homologues Bcl-3 and MAIL. It is a characteristicfeature of NF-κB that two of its subunits, p50and p52, are formed by proteolytic proteasomal processingof their precursor proteins, p105 and p100,respectively. Unprocessed p105 and p100 bind to otherNF-κB subunits and so act as cytoplasmic inhibitors.There are two distinct IKK pathways, which respond toextracellular stimuli and either trigger degradation ofIκBs and liberation of prototypic p50-p65 (canonicalpathway) or proteolytic processing of p100 and productionof p52-RelB complexes (non-canonical pathway)(Figure 1). The two pathways depend on IKKβ andIKKγ/NEMO or on IKKα, respectively. For the canonicalpathway, a critical role for non-degradative, K63-linkedpoly-ubiquitination has been recognized. These ubiquitinmodifications are generated by ubiquitin ligases,such as TRAF2 or TRAF6, and enforce a co-recruitment ofthe IKK complex and other components, which haveubiquitin binding motifs, to receptor-proximal complexes.This results in T-loop phosphorylation and activationof IKKs. A third IKK pathway is activated by DNAdamage-inducing agents or conditions, such as γ-irradiationor chemotherapeutic drugs in the nucleus and78 Cancer Research