Cell Memory in the Mitogen-Activated Protein Kinase Signaling Pathway

Cells process information from their environment, such as the stimuli to grow, divide, or die, via cell signaling. Deregulated processing of extracellular stimuli can lead to aberrant cell responses and cause cancer. Given that the in vivo cell environment constantly changes, it is important to understand how cells incorporate the context of their environment into their decision making processes. The idea of responding to relative, not absolute, changes in stimuli was first proposed in studies of human perception and became known as Weber's Law. Although, evidence of Weber's Law at the molecular level has been previously presented in studies of several organisms, to the best of our knowledge, it has never been explored in the case of relative sensing of extracellular stimuli in mammalian signaling cascades. The Mitogen-Activated Protein Kinase (MAPK) signaling pathway has been implicated in multiple human diseases, including cancers, and therefore cell signaling through this pathway is an important subject of research. Here we present a theoretical framework and an experimental validation of the mechanism of Weber's Law in the ability of cells to sense relative changes in the levels of extracellular stimuli in the MAPK signaling pathway. In particular, in this work we consider relative sensing in levels of Epidermal Growth Factor (EGF) in the MAPK pathway. We derive an analytical model of steady state behavior of the MAPK signaling pathway stimulated with constant doses of EGF. We demonstrate a mechanism that produces phosphorylation responses proportional to relative changes in ligand concentrations. The mechanism of Weber's Law presented here entails the retention of memory of the dose of the past chronic stimulation with EGF. The molecular mechanisms responsible for Weber's Law in MAPK signaling are likely to contribute to many other receptors signaling systems. Therefore, the mechanism of relative sensing of extracellular ligand concentrations derived here can be generalized beyond the EGF-activated MAPK signaling pathway to many other cell signaling systems. This thesis also presents a probabilistic framework to explore the parameter space of a detailed mechanistic ODE model of EGFR signaling cascades. The application of the model simulation allows us to generate probabilistic predictions of EGFR system behavior and to explore structure-to-function relationships between the model's parameter space and EGFR system responses. Overall, this work suggests an alternative view on the role of cellular endocytosis in the MAPK signaling in vivo. Specifically, traditionally viewed as a mechanism to downregulate and terminate cell signaling, endocytosis may enable cells to dynamically adjust their sensitivity to extracellular stimuli, and hence allow cells to integrate information about the past stimulations into the cell responses to the consequent stimulations and thus, cell fate decisions

Data mining for proteins characteristic of clades

A synapomorphy is a phylogenetic character that provides evidence of shared descent. Ideally a synapomorphy is ubiquitous within the clade of related organisms and nonexistent outside the clade, implying that it arose after divergence from other extant species and before the last common ancestor of the clade. With the recent proliferation of genetic sequence data, molecular synapomorphies have assumed great importance, yet there is no convenient means to search for them over entire genomes. We have developed a new program called Conserv, which can rapidly assemble orthologous sequences and rank them by various metrics, such as degree of conservation or divergence from out-group orthologs. We have used Conserv to conduct a largescale search for molecular synapomorphies for bacterial clades. The search discovered sequences unique to clades, such as Actinobacteria, Firmicutes and γ-Proteobacteria, and shed light on several open questions, such as whether Symbiobacterium thermophilum belongs with Actinobacteria or Firmicutes. We conclude that Conserv can quickly marshall evidence relevant to evolutionary questions that would be much harder to assemble with other tools