Erythropoietin (EPO) is a glycoprotein cytokine known for its pleiotropic effects on various types of cells and tissues. EPO and its receptor EPOR trigger signaling cascades JAK2/STAT5, MAPK, and PI3K/AKT that are interconnected and irreplaceable for cell survival. In this article, we describe the role of the MAPK and PI3K/AKT signaling pathways during red blood cell formation as well as in non-hematopoietic tissues and tumor cells. Although the central framework of these pathways is similar for most of cell types, there are some stage-specific, tissue, and cell-lineage differences. We summarize the current state of research in this field, highlight the novel members of EPO-induced PI3K and MAPK signaling, and in this respect also the differences between erythroid and non-erythroid cells.

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Here we demonstrate an interaction between neural precursor cell expressed, developmentally-downregulated 9 (NEDD9) and the cytoskeletal proteins vimentin and non-muscle myosin IIA (NMIIA), based on co-immunoprecipitation and mass spectrometric sequence identification. Vimentin was constitutively phosphorylated at Ser56 but vimentin associated with NEDD9-was not phosphorylated at Ser56. In contrast, NMIIA bound to NEDD9 was phosphorylated on S1943 consistent with its function in invasion and secretion. Treatment of cells with the vimentin-targeting steroidal lactone withaferin A had no effect on vimentin turnover as previously reported, instead causing NEDD9 cleavage and cell death. The NMIIA-selective inhibitor blebbistatin induced cells to form long extensions and attenuated secretion of matrix metalloproteinases (MMPs) 2 and 9. While the site of vimentin interaction on NEDD9 was not defined, NMIIA was found to interact with NEDD9 at its substrate domain. NEDD9 interactions with vimentin and NMIIA are consistent with these proteins having roles in MMP secretion and cell invasion. These findings suggest that a better understanding of NEDD9 signaling is likely to reveal novel therapeutic targets for the prevention of invasion and metastasis.

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Mass hibernacula of several tens of thousands of