Joseph Avruch

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..This interplay between overexpressed YAP and β-catenin also drives proliferation of colon cancer cells. The dispensability of YAP in normal intestine makes YAP's expression or outputs attractive targets for cancer therapy...

..In this review, we discuss the role of Hippo signalling in liver biology and the contribution of this pathway to liver cancer in humans...

..The components of the insulin/IGF pathway to TORC1 are now well established, whereas the elements mediating the more ancient and functionally dominant input of amino acids remain largely unknown...

..The mechanism underlying this second step in the activation of mTORC1 is unknown...

..Herein, we review the binding of the Rassf polypeptides to Ras-like GTPases and the Mst1/2 kinases and their role in Rassf function...

..The discovery of these kinases is reviewed, followed by a discussion of some of the features of this signaling module that account for its broad impact on cell function and its enormous interest to many investigators...

..The type III phosphatidylinositol kinase also participates in amino acid-dependent mTORC1 activation, although the site of action of its product, 3'OH-phosphatidylinositol, in this process is unclear...

..The Tuberous Sclerosis heterodimer (TSC1/TSC2) functions as a Rheb GTPase activator and inhibits TOR signaling in vivo...

..NORE1, a noncatalytic polypeptide, binds specifically to Ras-GTP and to several other Ras-like GTPases. NORE is homologous to the putative tumor suppressor RASSF1 and to the Caenorhabditis elegans polypeptide T24F1.3...

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..Thus, in addition to its positive role in the proliferative outputs of active Ras, the CNK1 scaffold protein, through its binding of a RASSF1A.MST complex, also participates in the proapoptotic signaling initiated by active Ras...

..Approximately 30% of human HCCs show low Yap1(Ser127) phosphorylation and a majority exhibit loss of cleaved, activated Mst1. Mst1/2 inhibition of Yap1 is an important pathway for tumor suppression in liver relevant to human HCC...

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..We conclude that Rheb signaling to mTOR in vivo requires a Rheb switch 2-dependent interaction with an element other than the three known polypeptide components of TOR complex 1...

..The Nore1B/RAPL-Mst1 complex is a negative regulator of naïve T cell proliferation...

..Thus, during mitosis Nek6 phosphorylates a subset of Eg5 polypeptides at a conserved site, the phosphorylation of which is crucial for the mitotic function of Eg5...

..Thus, the Mst1 and Mst2 kinases control Rho GTPase activation and the migratory responses of SP thymocytes...

..At present, however, the relevance of Ki-Ras-induced apoptosis to the physiological functions of c-Ras and to the growth-regulating actions of spontaneously occurring oncogenic Ras mutants is not known...

..Amino acid withdrawal may generate an inhibitor of the Rheb-mTOR interaction that interferes with the signaling function of TOR complex 1...

..We propose that the NORE1/RASSF1 polypeptides, in addition to their role in maintaining the low activity of MST1 in vivo, direct MST1 to sites of activation and perhaps co-localization with endogenous substrates...

..These findings support the conclusion that Nercc1/Nek9 and Nek6 represent a novel cascade of mitotic NIMA family protein kinases whose combined function is important for mitotic progression...

..The dispensability of Yap1 in normal intestinal homeostasis and its potent proliferative and prosurvival actions when overexpressed in colon cancer make it an attractive therapeutic target...

..Thus, Nore1 suppresses the growth of some tumor cell lines through as yet unidentified effectors, independent of Ras-like proteins or MST1/2...

..MST1 is unable to directly phosphorylate p53, however, DAP4 binds endogenous and recombinant p53. DAP4 may promote MST1-induced apoptosis by enabling colocalization of MST with p53...

..Identifying previously unappreciated proteins needed for maintenance of mTORC1 activity may provide new targets and lead to the development of beneficial therapies for pancreatic cancer...

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..Thus, Nercc1 contributes to both the centrosomal and the chromatin/Ran pathways that collaborate in the organization of a bipolar spindle...

..We describe a C. elegans TOR homolog (CeTOR) and phenotypes associated with CeTOR deficiency. These phenotypes are compared with the response to starvation and the inactivation of a variety of putative TOR targets...

..Together, these data identify Yap1 as a determinant of the proliferative capacity of epidermal stem cells and as an important effector of a "crowd control" molecular circuitry in mammalian skin...

..The preferential ability of RASSF1A to heterodimerize with Nore and thereby associate with Ras-like GTPases may be relevant to its putative tumor suppressor function...

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..Thus, a mutation in Mst1 alone does not affect survival. Our results set the stage for identification of the lethal second-site mutation that is paradoxically favored for transmission...

..Doubly phosphorylated IMP2 is also widely expressed in adult tissues, including islets of Langerhans...

..Inasmuch as TORC2 is activated by association with ribosomes, the present results indicate that mTORC2-catalyzed cotranslational protein phosphorylation is a core function of this complex...

..Nercc1 and its partner Nek6 represent a new signaling pathway that regulates mitotic progression...

..The nuclear factor-kappa B pathway, a second stress signaling paradigm, has been the subject of several excellent recent reviews (258, 260)...

..These findings unveil the ability of GPCRs to activate the YAP oncogene through a newly recognized signaling function of the actin cytoskeleton, likely to be especially important for normal and cancerous stem cells...

..Herein we first summarize the molecular components of the mammalian stress-regulated MAPK pathways and their regulation as described thus far. We then review some of the in vivo functions of these pathways...

..We conclude that mTOR is an upstream regulator of eIF-4E BP1 as well as the p70 S6 kinase; moreover, these two mTOR targets are regulated in a parallel rather than sequential manner...

..9). SAPKs therefore define a new TNF-alpha and stress-activated signalling pathway, possibly initiated by sphingomyelin-based second messengers, which regulates the activity of c-Jun...

..Acquisition of S6 protein kinase catalytic function, however, is apparently restricted to the most extensively phosphorylated recombinant polypeptides...

..One pathway for RTK control involves the tuberous sclerosis complex, which is absent in C. elegans, but of major importance in Drosophila and higher metazoans...

..We will then review in more detail current understanding of the biochemical mechanism through which the Ras proto-oncogene, in collaboration with the 14-3-3 protein and other protein kinases, initiates activation of the Raf kinase...

..Thus, these sequences of p70 S6 kinase constitute a potential autoinhibitory pseudosubstrate site, whose phosphorylation is catalyzed by candidate upstream-activating protein kinases...

..g.,Thr412 in p70 S6 kinase (alpha 1). Phosphorylation of the former site is catalyzed by PDK1, whereas the kinase responsible for the phosphorylation of the latter site is not known...

..Thus, hormonal regulation of S6 kinase may involve the action of MPF/cdc-2 or protein kinases with related substrate specificity...

..These results suggest that the cellular response to IR may include regulation of SAP kinase by a PI 3-kinase-dependent signaling pathway...

..Our data suggest that we have identified a novel mTOR interactor, ubiquilin 1. The biological significance of this, presumably membrane based, interaction, requires further study...

..Activation of the SAPK pathway by GCK illustrates further the striking conservation of eukaryotic signalling mechanisms and defines the first physiological function of a mammalian Ste20...

..In addition, Raf polypeptides bound to truncated 14.3.3 polypeptides are unable to undergo activation in situ, indicating that 14.3.3 participates in the process of Raf activation by mechanisms that remain to be elucidated...

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..These results indicate that c-Raf-1 is an immediate upstream activator of MAPK-K in vivo. To our knowledge, MAPK-K is the first physiological substrate of the c-raf-1 protooncogene product to be identified...

..Nore1 becomes associated with Ras in situ following activation of epidermal growth factor receptor in COS-7 and in KB cells...

..ABP-280 participates in TNF-alpha signal transduction to SAPKs, in part through the binding of SEK-1...

..Raf-1 (1-257) binds GTP-Ras in preference to GDP-Ras, and inhibits Ras-GAP activity. Mutations in and around the Ras effector domain impair Ras binding to Raf-1 (1-257) and Ras transforming activity in parallel...

..Thus, phosphovimentin, by sequestering 14-3-3 and limiting its availability to other target proteins can affect intracellular signaling processes that require 14-3-3...

..Taken together, our findings suggest that the Rictor-Myo1c complex is distinct from mTORC2 and that Myo1c, in conjunction with Rictor, participates in cortical actin remodeling events...

..elegans raptor yields an array of phenotypes that closely resemble those produced by inactivation of Ce-TOR. Thus, raptor is an essential scaffold for the mTOR-catalyzed phosphorylation of 4EBP1 and mediates TOR action in vivo...

..Moreover, they indicate that the ability of raptor to bind endogenous substrates is limiting for the activity of mTORC1 in vivo and is therefore a potential locus of regulation...

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..These findings establish a significant role of 14-3-3 dimerization in its ability to bind targets in a phosphorylation-dependent manner and point to a mechanism in which 14-3-3 phosphorylation and dimerization counterregulate each other...

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..However, aberrations in tumors have so far not been found. The presence of a Ras association domain common to NORE1, RASSF1, and RASSF3 suggests their possible involvement in Ras-like signaling pathways...

..Finally, we will characterize in vitro the basis for the radically different TOR kinase activity toward p70 S6K and 4E BP, and seek to identify the molecular basis for mTOR regulation in vivo. ..

..These results will have implications for the design of new pharmacologic interventions in diabetes mellitus and will have wide implications for the nutritional regulation of body protein turnover. ..

..The results of these studies will provide a basis for therapeutic interventions in this pathway, which is crucial to both human cancers and to diseases like Type 2 diabetes ..

..The institutional training grant represents the central stabilizing financial element in this program, and is especially critical in enabling M.D. trainees to achieve careers in biomedical investigation ..

..The results of these studies will provide basis for therapeutic interventions in this pathway, which is crucial to both human cancers and to diseases like Type 2 diabetes ..

..We want to find out how they are regulated, the identity of their key targets in suppressing tumor development, how their removal enables liver cancer to develop and their role in human liver cancer. ..

..These studies will define a new signal transduction pathway controlling cell growth in lymphoid and other cells. ..

..The results of these studies will provide basis for therapeutic interventions in this pathway, which is crucial to both human cancers and to diseases like Type 2 diabetes ..