Titolo della tesi: Impact of ERK2 missense variants found in cancer: structural, function and stability experimental analysis
The extracellular-signal-regulated kinase (ERK2) participates in the Ras-Raf-MEK-ERK signal transduction cascade involved in the regulation of a large variety of cellular processes. ERK2 is the principal effector of a central signaling cascade that converts extracellular stimuli into cell proliferation and migration responses and, when deregulated, can promote cell oncogenic transformation. The deviation from the strict control of ERK2 signaling pathways has been implicated in the development of many human diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and various types of cancers. Several ERK2 variants have been identified in cancer tissues as nonsynonymous single nucleotide variants (nsSNVs) that occur in the DNA coding region and encode a change in the amino acid sequence. This thesis reports the collection of structural, function and stability data of unphosphorylated (NP-) and phosphorylated (P-)ERK2 wild type and 17 somatic variants. A detailed understanding of the changes of the investigated gene products, at the molecular level, to assess how genetic variations impact the protein folding, structure, functions, and interactions is required to develop new therapeutic strategies, particularly in the search of small molecules able to selectively interact with the variants: that is an essential preliminary step to personalized medicine, and help to identify new potential therapeutic targets.