Molecular mechanisms of CIB1 signaling

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ABSTRACT CIB1 is an intracellular protein that regulates cell growth, survival and proliferation, most notably under pathologic conditions. It functions by binding directly to effector kinases, integrins and other targets and modulates their activity, thereby serving as a signaling node for key regulatory pathways. Inhibition of CIB1 binding to select partners has excellent therapeutic potential in multiple diseases such as cancer, retinopathies and cardiac hypertrophy. It is therefore critical to understand CIB1 signaling in different cell types. In many breast cancer cell lines but not in normal cells tested to date, CIB1 is required for survival and proliferation via the PI3K/AKT and MEK/ERK pathways. In endothelial cells, CIB1 supports efficient angiogenesis in response to injury via the MEK/ERK pathway. However, how and why CIB1 selectively regulates these pathways under stressed or transformed conditions is poorly understood. We found that CIB1 interacts directly with PAK1 and PDK1, which can feed into these pathways. Moreover, while some data suggest that CIB1 regulates integrin signaling, which can activate the PI3K/AKT and MEK/ERK pathways, it is completely unknown whether or how CIB1 connects integrin signaling to these pathways. Our overall hypothesis is that under select stress or oncogenic conditions in a variety of cell types, CIB1 binds to specific partners to regulate the PI3K/AKT, MEK/ERK and potentially other pathways, to promote cell viability, growth and proliferation. To address this hypothesis, we will use a combination of targeted and unbiased approaches to determine how the CIB1 interaction with PAK1, PDK1 and the αV integrin support the PI3K/AKT and MEK/ERK pathways. We will complement targeted approaches with unbiased phosphoproteomics and interactomics to delineate on a global scale, how CIB1 signaling affects not only MEK/ERK and PI3K/AKT but other phospho-signaling pathways that may help explain CIB1 biology.