No abstract

During development, Drosophila larvae undergo a dramatic increase in body mass wherein nutritional and developmental cues are transduced into growth through the activity of complex signaling pathways. Class I phosphoinositide 3-kinases have an established role in this process. In this study we identify Drosophila phosphatidylinositol 5-phosphate 4-kinase (dPIP4K) as a phosphoinositide kinase that regulates growth during larval development. Loss-of-function mutants in dPIP4K show reduced body weight and prolonged larval development, whereas overexpression of dPIP4K results both in an increase in body weight and shortening of larval development. The growth defect associated with dPIP4K loss of function is accompanied by a reduction in the average cell size of larval endoreplicative tissues. Our findings reveal that these phenotypes are underpinned by changes in the signaling input into the target of rapamycin (TOR) signaling complex and changes in the activity of its direct downstream target p70 S6 kinase. Together, these results define dPIP4K activity as a regulator of cell growth and TOR signaling during larval development.

SUMMARY PARK2 is a gene implicated in disease states with opposing responses in cell fate determination, yet its contribution in pro-survival signaling is largely unknown. Here, we show that PARK2 is altered in over a third of all human cancers and its depletion results in enhanced PI3K/Akt activation, and increased vulnerability to PI3K/Akt/mTOR inhibitors. PARK2 depletion contributes to AMPK-mediated activation of eNOS, enhanced levels of reactive oxygen species and a concomitant increase in oxidized nitric oxide levels, thereby promoting inhibition of PTEN by S-nitrosylation and ubiquitination. Notably, AMPK activation alone is sufficient to induce PTEN S-nitrosylation in the absence of PARK2 depletion. Park2 and Pten loss also display striking cooperativity to promote tumorigenesis in vivo. Together, our findings reveal an important missing mechanism that might account for PTEN suppression in PARK2-deficient tumors and highlight the importance of PTEN S-nitrosylation in supporting cell survival and proliferation under conditions of energy deprivation.

Evolving semiconductor and circuit technology has greatly increased the pin bandwidth available to a router chip. In the early 90s, routers were limited to 10Gb/s of pin bandwidth. Today 1Tb/s is feasible, and we expect 20Tb/s of I/O bandwidth by 2010. A high-radix router that provides many narrow ports is more effective in converting pin bandwidth to reduced latency and reduced cost than the alternative of building a router with a few wide ports. However, increasing the radix (or degree) of a router raises several challenges as internal switches and allocators scale as the square of the radix. This paper addresses these challenges by proposing and evaluating alternative microarchitectures for high radix routers. We show that the use of a hierarchical switch organization with per-virtual-channel buffers in each subswitch enables an area savings of 40% compared to a fully buffered crossbar and a throughput increase of 20-60% compared to a conventional crossbar implementation.