Jonathan Backer

..In this issue of the Biochemical Journal, Sarkes and Rameh describe a novel HPLC-based approach which makes possible an analysis of the subcellular distribution of PtdIns5P and other phosphoinositides...

..Thus Class III PI3Ks are implicated in the regulation of both autophagy and, through the mTOR pathway, protein synthesis, and thus contribute to the integration of cellular responses to changing nutritional status...

..Our data suggest that Cdc42 activation is crucial for the regulation of actin polymerization in carcinoma cells, and required for both EGF-stimulated protrusion and cell motility independently of effects on Rac...

..These data describe a novel role for Rho in coordinating signaling by Rac and Cdc42...

..These data suggest an unappreciated role for Ras during protrusion, and a crucial role for Rac in the stabilization of protrusions required for cell motility...

..Thus, we find differing spatial scales of signaling from the EGF receptor, supporting models of chemotaxis that integrate short- and long-range signaling...

..Our data suggest that hVps34 is a nutrient-regulated lipid kinase that integrates amino acid and glucose inputs to mTOR and S6K1...

..These data show that coordinate regulation between the WASP family and mDia proteins controls the balance between lamellar and lamellipodial protrusion activity...

..The coupling doubling, however, is independent of the magnetic field strength and a signature feature of the 2Q coherence. The ramification of the relative relaxation rates of 1Q and 2Q coherences is discussed...

..Moreover, our data provide evidence for how PLC is involved in the formation of protrusions in breast carcinoma cells during chemotaxis and metastasis towards EGF...

..The changes in cell shape, directional migration, and turning frequency were related to the re-localization of Arp2/3 complex to one pole of the cell upon suppression of cofilin expression...

..These results suggest that activation of hypothalamic S6K contributes to hepatic insulin resistance in response to short-term nutrient excess...

..The complex web of signaling downstream from Class IA PI 3-kinases will be discussed in other chapters in this volume...

..Therefore, our results demonstrate that the early PLC and cofilin-dependent barbed end transient is required for the initiation of protrusions and is involved in setting the direction of cell movement in response to EGF...

..Identification of effectors that are differently regulated by p110alpha versus p110beta will be important for understanding cell migration and its role in metastasis...

..These data suggest that PLCgamma is involved in a negative feedback loop that leads to the inhibition of Rac and Cdc42. They also suggest that the presence of intracellular calcium is a prerequisite for both Rac and Cdc42 activation...

..These data suggest that anti-PtdIns(3,4,5)P(3) antibodies are a useful tool to detect localized PtdIns(3,4,5)P(3), and illustrate the importance of using multiple approaches for the estimation of membrane phosphoinositides...

..Our observations suggest that, when compared with kinase domain mutations in a genetically identical background, expression of helical domain mutants of p110alpha produce a more severe metastatic phenotype...

..Based on these findings, we propose a general model for oncogenic mutants of p85 and p110 in which disruption of nSH2-p110 regulatory contacts leads to constitutive p110 activity...

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..These data suggest that the YXXM motifs in the PDGFR serve two distinct functions: PI 3-kinase recruitment and lysosomal targeting...

..These data support a model in which the iSH2 domain is a rigid tether for p110, and regulation of p85/p110 is mediated by nSH2-p110 contacts...

..The results of the present study show that, in mammalian cells, hVps34 activity is regulated through its interactions with hVps15, but is independent of Ca2+/CaM...

..Thus, our data suggests that mutations at the C2-iSH2 domain contact and truncations of the iSH2 domain, which are found in human tumors, both act by disrupting the C2-iSH2 domain interface...

..These data have important implications for the mechanism by which p85/p110 dimers are regulated by phosphopeptides...

..The inter-SH2 domain is assigned as a rigid anti-parallel coiled-coil whose primary function is to bind p110, facilitating inhibition of p110 by the N-terminal SH2 domain of p85...

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..Elucidation of the intersections between these distinct pathways will lead to new insights into mast cell degranulation...

..However, Rab5 does not appear to act by directly recruiting p150/hVps34 complexes from the cytosol to the endosomal membrane...

..Thus, MAP-2c can directly recruit multiple signaling proteins important for central nervous system development...

..Our results show that autophagy is under strict mitotic control and indicate a novel role for phosphoinositide 3-kinases or other wortmannin/LY294002-sensitive kinases in mitotic membrane traffic regulation...

..These findings indicate an unexpected role for p110beta catalytic activity in diabetes and cancer, opening potential avenues for therapeutic intervention...

..Thus, our data suggest that Wrch-1 regulates cell migration by multiple mechanisms: on the one hand Wrch-1 controls focal adhesions by regulating myosin light chain and on the other hand Wrch-1 stimulates the activation of Akt and JNK...

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..Thus, our findings suggest that receptor endocytosis is dispersible for TGF-beta-mediated activation of Smad2 and that this activation can be mediated by both SARA-dependent and -independent mechanisms...

..This chapter describes the analysis of hVps34/hVps15 interactions with Rab5 in tissue culture cells and in vitro...

..These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer...

..Our results suggest that Vps34 is regulated by TOR-dependent nutrient signals directly at sites of autophagosome formation...

..Understanding the mechanisms that regulate their activity in normal and malignant cells is critical for the design of novel and specific drugs to target these enzymes in human disease. ..

..Completion of these aims will greatly increase our understanding of the p85/p110 PI 3-kinase, and lead to mechanistic insights into its activation in human cancer. ..

..Overall, these studies will have important implications for our understanding of the function and regulation of hVps34, and its role in insulin action and diabetes. ..

..Completion of these aims will greatly increase our understanding of the p85/p110 PI 3-kinase, and lead to mechanistic insights into its activation in human cancer. ..

..Overall, these studies will have important implications for our understanding of the function and regulation of hVps34, and its role in insulin action and diabetes. ..

..Completion of these aims will greatly increase our understanding of the p85/p110 PI 3-kinase, and lead to mechanistic insights into its activation in human cancer. ..

..Successful completion of these experiments will substantially advance our understanding of signal transduction by this critical and physiologically important signaling enzyme. ..

..Overall, these studies will have important implications for our understanding of the function and regulation of hVps34, and its role in insulin action and diabetes. ..