Substrate Selectivity APPLies to Akt

The protein kinase Akt occupies a central position in multiple signaling pathways. Although numerous Akt substrates have been identified, less is known about the factors that regulate specific cellular responses to Akt signaling. In this issue, Schenck et al. (2008) demonstrate that the endosomal protein Appl1 modulates Akt's substrate selectivity to promote cell survival during zebrafish development

The mitogen activated protein kinase signal transduction pathway: From the cell surface to the nucleus

Activation of the mitogen activated protein kinase (MAPK) plays esential roles in many signal transduction pathways. MAPK has been demonstrated to phosphorylate and regulate numerous cellular proteins, including growth factor receptor, transcription factors, cytoskeletal proteins, phospholipase and other protein kinases. Activation of MAPK requires phosphorylation of both threonine and tyrosine residues, which are catalysed by a single protein kinase known as MAPK kinase or MEK. MEK itself is activated by phosphorylation on two conserved serine residues. Three distinct mammalian Ser/Thr kinases, including Raf, Mos and MEKK (for MEK kinase), have been demonstrated to phosphorylate and activate MEK. The MAP kinase cascade is highly conserved in all eukaryotes and involved in numerous cellular responses. Activation of MAPK is a transient event that is tightly regulated by both kinases and phosphatases. A growth factor induced dual specific phosphatase is likely to play an important role in MAPK regulation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31420/1/0000337.pd

The Vam6 and Gtr1-Gtr2 pathway activates TORC1 in response to amino acids in fission yeast

The Rag family of GTPases has been implicated in the TORC1 activation in Drosophila and in mammalian cells in response to amino acids. We have investigated the role of the Rag GTPases Gtr1 and Gtr2 in TORC1 regulation in Schizosaccharomyces pombe. Fission yeast Gtr1 and Gtr2 are non-essential proteins that enhance cell growth in the presence of amino acids in the medium. The function of Gtr1 and Gtr2 in nutrient signaling is further supported by the observation that even in rich medium the deletion of either gene results in the promotion of mating, meiosis and sporulation, consistent with the downregulation of TORC1. We show that Gtr1 and Gtr2 colocalize with TORC1 in vacuoles, where TORC1 is presumably activated. Epistasis analyses indicated that Gtr1 and Gtr2 function downstream of Vam6 and upstream of TORC1 in response to amino acid signals. Our data demonstrate the existence of an evolutionarily conserved pathway with the Vam6 and Gtr1-Gtr2 pathway activating TORC1, which in turns stimulates cell growth and inhibits sexual differentiation. © 2012.This work is supported by grants from Ministerio de Economía y Competitividad [grant numbers BFU2008-01808, BFU2011-28274, Consolider CSD2007-00015] and Junta de Castilla y León Grupo de Excelencia [grant number GR 265] to S.M. N.V. is supported by a postdoctoral grant from the Carlos III Institute, Ministerio de Sanidad.Peer Reviewe

Mst Out and HCC In

Mst1 and Mst2 are key components of the Hippo tumor suppressor pathway. In this issue, Zhou et al. (2009) reported that Mst1/2 ablation leads to hepatocellular carcinomas. Unexpectedly, Mst1/2 may activate another kinase besides Lats1 and Lats2 to phosphorylate YAP, and the role of Mst1/2 in YAP regulation is cell type dependent

Homologous recombination repair pathway alteration and its association with survival of breast cancer patients

Breast cancer is a highly heterogeneous neoplasm with different response to chemotherapy. In this study, we investigated if homologous recombination repair (HRR), one of the important pathways of DNA damage repair, could serve as biomarkers for breast cancer. Breast cancer patients were selected from the Cancer Genome Atlas (TCGA) database.  Data of RNA-seq or mutation alteration of HRR pathway-related genes were extracted and analyzed. Correlations between HRR pathway mutation and clinicopathological features of breast cancer were analyzed using chi-square test. Based on the Kaplan-Meier method and log-rank test, survival analysis was done to identify the correlation between each HRR gene and survival rates. Using data retrieved from TCGA database, 1108 cases were identified of breast cancer with full data on RNA-seq and 986 cases with full data on mutation. We demonstrated that high expression of HRR gene RAD50, RAD51, RAD51C, RAD54L and XRCC2 were associated with favorable prognosis (Log-rank P=0.02686, 0.03734, 0.00664, 0.01147 and 0.01818, respectively). Moreover, mutation in the HRR pathway was present in 15.0% of cases. RIM1, PPP4R2, PPP4R4, RAD50 and RAD51D gene mutation were associated with unfavorable outcome (Log-rank P=0.0346, 0.0051, 0.0326, 0.0213 and 0.0007, respectively). The N stage and estrogen receptor (ER) status were significantly related to HRR pathway mutation (all factors P<0.05). Additionally, basal-like breast cancer subtype took up more percentage in HRR pathway mutation patients. Low expression or mutation in HRR pathway were associated with unfavorable prognosis in breast cancer. HRR pathway could serve as potential predictor, emphasizing the significance of more research on HRR pathway genes to facilitate more profound clinical implications in breast cancer molecular treatment.   DOI: 10.14800/rd.46

Organ Size Control by Hippo and TOR Pathways

The determination of final organ size is a highly coordinated and complex process that relies on the precise regulation of cell number and/or cell size. Perturbation of organ size control contributes to many human diseases, including hypertrophy, degenerative diseases, and cancer. Hippo and TOR are among the key signaling pathways involved in the regulation of organ size through their respective functions in the regulation of cell number and cell size. Here, we review the general mechanisms that regulate organ growth, describe how Hippo and TOR control key aspects of growth, and discuss recent findings that highlight a possible coordination between Hippo and TOR in organ size regulation

Mechanistic insights into the regulation of metabolic enzymes by acetylation

The activity of metabolic enzymes is controlled by three principle levels: the amount of enzyme, the catalytic activity, and the accessibility of substrates. Reversible lysine acetylation is emerging as a major regulatory mechanism in metabolism that is involved in all three levels of controlling metabolic enzymes and is altered frequently in human diseases. Acetylation rivals other common posttranslational modifications in cell regulation not only in the number of substrates it modifies, but also the variety of regulatory mechanisms it facilitates

Regulation of intermediary metabolism by protein acetylation

Extensive studies during the past four decades have identified important roles for lysine acetylation in the regulation of nuclear transcription. Recent proteomic analyses on protein acetylation uncovered a large number of acetylated proteins in the cytoplasm and mitochondria, including most enzymes involved in intermediate metabolism. Acetylation regulates metabolic enzymes by multiple mechanisms, including via enzymatic activation or inhibition, and by influencing protein stability. Conversely, non-nuclear NAD+-dependent sirtuin deacetylases can regulate cellular and organismal metabolism, possibly through direct deacetylation of metabolic enzymes. Furthermore, acetylation of metabolic enzymes is highly conserved from prokaryotes to eukaryotes. Given the frequent occurrence of metabolic dysregulation in diabetes, obesity, and cancer, enzymes modulating acetylation could provide attractive targets for therapeutic intervention for these diseases

Modulation of KSR activity in Caenorhabditis elegans by Zn ions, PAR‐1 kinase and PP2A phosphatase

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102112/1/emboj7600025.pd

Identification of FIP200 interaction with the TSC1–TSC2 complex and its role in regulation of cell size control

FIP200 (focal adhesion kinase [FAK] family interacting protein of 200 kD) is a newly identified protein that binds to the kinase domain of FAK and inhibits its kinase activity and associated cellular functions. Here, we identify an interaction between FIP200 and the TSC1–TSC2 complex through FIP200 binding to TSC1. We found that association of FIP200 with the TSC1–TSC2 complex correlated with its ability to increase cell size and up-regulate S6 kinase phosphorylation but was not involved in the regulation of cell cycle progression. Conversely, knockdown of endogenous FIP200 by RNA interference reduced S6 kinase phosphorylation and cell size, which required TSC1 but was independent of FAK. Furthermore, overexpression of FIP200 reduced TSC1–TSC2 complex formation, although knockdown of endogenous FIP200 by RNA interference did not affect TSC1–TSC2 complex formation. Lastly, we showed that FIP200 is important in nutrient stimulation-induced, but not energy- or serum-induced, S6 kinase activation. Together, these results suggest a cellular function of FIP200 in the regulation of cell size by interaction with the TSC1–TSC2 complex