Toll-benzeri reseptörlerin yapısal yolaklarını oluşturarak kanser ile enflamasyon arasındaki ilişkiyi anlamak

Toll-like receptor (TLR) pathway is one of the major pathways that give rise to inflammation, which is the first line of defense against pathogens. Although it is essential for host defense, inflammation also contributes to almost all phases of tumor development. TLR pathway plays a key role in inflammation-cancer crosstalk, but the exact mechanisms how they contribute to this remain elusive. Construction of structural TLR pathway provides insights into its roles in this crosstalk. The classical node-and-edge representation of pathways provides the big picture in a simple way, but it is incomplete. Structural pathways can help complete missing parts of such diagrams: they can help in understanding how an upstream signal is transduced to downstream; how higher-order oligomerization modes of proteins can influence their function; how mutations, inhibitors or antagonists affect the signaling and change cellular outcome; and which alternative parallel pathways can be activated simultaneously. Constructing structural pathways is a challenging task. In this dissertation, I constructed structural network of TLR pathway by employing the powerful PRISM (PRotein Interactions by Structural Matching) algorithm and available mutational/biochemical data. I built the structural network of TLR pathway; its regulatory pathways; and also other pathways that have important roles in inflammation-cancer relation, such as different cytokine pathways, and CASP8, and TRAF3 centered pathways. The architectures that I obtained provide the structural basis for TLR clustering upon stimulation and assembly of key signaling complexes, such as "TIR domain signalosome". They also demonstrate that almost all downstream parallel pathways of TLRs are competitive and clarify decisions at pathway branching points. I showed that several negative regulators restrict TLR signaling by interfering with the formation of the key interactions and signalosomes. I also performed in silico mutagenesis analysis to characterize the effects of oncogenic mutations and found that some mutations that fall on the interfaces disrupt the interactions with their targets and enable constitutive activation of NF-κB, which might lead to chronic inflammation, which promotes oncogenesis. Our results help to understand the crosstalk between cancer and inflammation from a structural perspective.