of samples to cover different isoforms of PLA2s. Since there are more than 30 PLA2s, none of the previous studies provide an overall picture of PLA2s in any cancer. More importantly, their enzymatic activities, but not necessarily their RNA and/or protein expression levels, are directly related to the biological effects, since PLA2 activities are well-known to be regulated post-transcriptionally. This concept has been supported in our recent pre-clinical and human sample studies in ovarian cancer and remain to be tested further in other cancers. ~~ ~~ The differentiation of naive T cells into specialized 21147071 effector, memory, and regulatory T cells, is critical for mounting an appropriate immune response to pathogens, and tumors as well as for maintaining tolerance to self. The mammalian target of rapamycin is a conserved serine/threonine kinase that has been implicated in many of these MedChemExpress DCC 2618 events. mTOR plays a role in peripheral tolerance, as mTOR inhibition during T cell activation can lead to anergy, as well as promote the differentiation of CD4+ T cells into regulatory T cells . In contrast, mTOR signaling is required for the differen tiation of naive CD4+ T cells into Th1, Th2 and Th17 effector T cells. Finally, inhibition of mTOR promotes the differentiation of memory CD8+ T cells, as treatment of mice with the mTOR inhibitor rapamycin during infections with viruses and bacteria improves the generation and maintenance of pathogenspecific memory CD8+ T cells. mTOR is present in two different complexes called mTOR complex 1 and mTOR complex 2. Each complex contains a distinct scaffold protein such as regulatoryassociated protein of mTOR and rapamycin-insensitive companion of mTOR in mTORC1 and mTORC2, respectively. The requirement for mTORC1 versus mTORC2 in T cells varies with cell type. For example, mTORC1 is required for Th17 and CD8+ memory T cell differentiation, whereas mTORC2 is required for Th2 differentiation. Inhibition of both mTORC1 and mTORC2 is required for the enhanced generation of Tregs. In T cells, as in other eukaryotic cells, mTOR is activated in response to environmental cues, such as growth factors, and metabolic cues, such as nutrients. However, mTOR is also activated in T cells in response to signals such as TCR engagement, co-stimulation, and cytokines. Two main pathways have been described to regulate mTORC1 activation in T cells, namely the AMP-activated protein kinase pathway and the phosphoinositide 3-kinase -AKT pathway. The response to both signaling pathways are integrated by the tuberous sclerosis 1 tuberous sclerosis 2 complex. When active, the TSC1/TSC2 complex acts as a GTPase activating protein for Rheb, a crucial activator of mTORC1. Inactivation of Rheb by the TSC1/2 complex therefore inhibits 16873882 mTORC1 signaling. Phosphorylation of TSC2 by AKT inhibits its GAP activity, whereas phosphorylation of TSC2 by AMPK stimulates it. This explains how AKT activates and AMPK inactivates mTORC1. In other cell types, additional pathways, such as the ERK/ mitogen-activated protein kinase pathway, have been shown to regulate mTORC1 activation. ERK is activated in response to growth factors and can directly phosphorylate TSC2, disrupting the TSC1/TSC2 complex, thereby increasing mTOR 
activity. ERK can also phosphorylate p90 ribosomal protein S6 kinase, which phosphorylates TSC2. While it is known that during T cell activation, ERK is activated and recruited to the immunological synapse, it is unknown if ERK regulates m