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Morris J. Birnbaum – One of the best experts on this subject based on the ideXlab platform.

  • Akt is required for Stat5 activation and mammary differentiation
    Breast Cancer Research, 2010
    Co-Authors: Chien-chung Chen, Morris J. Birnbaum, Robert B Boxer, Douglas B Stairs, Carla P Portocarrero, Rachel H Horton, James V Alvarez, Lewis A Chodosh
    Abstract:

    Introduction The Akt pathway plays a central role in regulating cell survival, proliferation and metabolism, and is one of the most commonly activated pathways in human cancer. A role for Akt in epithelial differentiation, however, has not been established. We previously reported that mice lacking Akt1 , but not AKT2 , exhibit a pronounced metabolic defect during late pregnancy and lactation that results from a failure to upregulate Glut1 as well as several lipid synthetic enzymes. Despite this metabolic defect, however, both Akt1 -deficient and AKT2 -deficient mice exhibit normal mammary epithelial differentiation and Stat5 activation. Methods In light of the overlapping functions of Akt family members, we considered the possibility that Akt may play an essential role in regulating mammary epithelial development that is not evident in Akt1 -deficient mice due to compensation by other Akt isoforms. To address this possibility, we interbred mice bearing targeted deletions in Akt1 and AKT2 and determined the effect on mammary differentiation during pregnancy and lactation. Results Deletion of one allele of AKT2 in Akt1 -deficient mice resulted in a severe defect in Stat5 activation during late pregnancy that was accompanied by a global failure of terminal mammary epithelial cell differentiation, as manifested by the near-complete loss in production of the three principal components of milk: lactose, lipid, and milk proteins. This defect was due, in part, to a failure of pregnant Akt1 ^ -/- ; AKT2 ^ +/- mice to upregulate the positive regulator of Prlr-Jak-Stat5 signaling, Id2, or to downregulate the negative regulators of Prlr-Jak-Stat5 signaling, caveolin-1 and Socs2. Conclusions Our findings demonstrate an unexpected requirement for Akt in Prlr-Jak-Stat5 signaling and establish Akt as an essential central regulator of mammary epithelial differentiation and lactation.

  • akt1 and AKT2 maintain hematopoietic stem cell function by regulating reactive oxygen species
    Blood, 2010
    Co-Authors: Marisa M Juntilla, Morris J. Birnbaum, Marco Calamito, Vineet Patil, Rohan P Joshi, Gary A Koretzky
    Abstract:

    Although AKT is essential for multiple cellular functions, the role of this kinase family in hematopoietic stem cells (HSCs) is unknown. Thus, we analyzed HSC function in mice deficient in the 2 isoforms most highly expressed in the hematopoietic compartment, AKT1 and AKT2. Although loss of either isoform had only a minimal effect on HSC function, AKT1/2 double-deficient HSCs competed poorly against wild-type cells in the development of myeloid and lymphoid cells in in vivo reconstitution assays. Serial transplantations revealed an essential role for AKT1 and AKT2 in the maintenance of long-term HSCs (LT-HSCs). AKT1/2 double-deficient LT-HSCs were found to persist in the G0 phase of the cell cycle, suggesting that the long-term functional defects are caused by increased quiescence. Furthermore, we found that the intracellular content of reactive oxygen species (ROS) is dependent on AKT because double-deficient HSCs demonstrate decreased ROS. The importance of maintaining ROS for HSC differentiation was shown by a rescue of the differentiation defect after pharmacologically increasing ROS levels in double-deficient HSCs. These data implicate AKT1 and AKT2 as critical regulators of LT-HSC function and suggest that defective ROS homeostasis may contribute to failed hematopoiesis.

  • Akt1 and AKT2 promote peripheral B-cell maturation and survival.
    Blood, 2009
    Co-Authors: Marco Calamito, Marisa M Juntilla, Gary A Koretzky, Morris J. Birnbaum, Jeffrey C Rathmell, Matthew B. Thomas, Daniel L. Northrup, David Allman
    Abstract:

    Although the 3 isoforms of Akt regulate cell growth, proliferation, and survival in a wide variety of cell types, their role in B-cell development is unknown. We assessed B-cell maturation in the bone marrow (BM) and periphery in chimeras established with fetal liver progenitors lacking Akt1 and/or AKT2. We found that the generation of marginal zone (MZ) and B1 B cells, 2 key sources of antibacterial antibodies, was highly dependent on the combined expression of Akt1 and AKT2. In contrast, Akt1/2 deficiency did not negatively affect the generation of transitional or mature follicular B cells in the periphery or their precursors in the BM. However, Akt1/2-deficient follicular B cells exhibited a profound survival defect when forced to compete against wild-type B cells in vivo. Altogether, these studies show that Akt signaling plays a key role in peripheral B-cell maturation and survival.

Michael Forgac – One of the best experts on this subject based on the ideXlab platform.

Michael Collins – One of the best experts on this subject based on the ideXlab platform.

  • akt ser thr kinase increases v atpase dependent lysosomal acidification in response to amino acid starvation in mammalian cells
    Journal of Biological Chemistry, 2020
    Co-Authors: Michael Collins, Laura A Stransky, Michael Forgac
    Abstract:

    The vacuolar H+-ATPase (V-ATPase) is an ATP-dependent proton pump that is essential for cellular homeostasis. V-ATPase activity is controlled by the regulated assembly of the enzyme from its component V1 and V0 domains. We previously reported that amino acid starvation rapidly increases V-ATPase assembly and activity in mammalian lysosomes, but the signaling pathways controlling this effect are unknown. In testing inhibitors of pathways important for controlling cellular metabolism, we found here that the cAMP-dependent protein kinase (PKA) inhibitor H89 increases lysosomal V-ATPase activity and blocks any further change upon starvation. The AMP-activated protein kinase (AMPK) inhibitor dorsomorphin decreased lysosomal V-ATPase activity and also blocked any increase upon starvation. However, CRISPR-mediated gene editing revealed that PKA and AMPK are not required for the starvation-dependent increase in lysosomal V-ATPase activity, indicating that H89 and dorsomorphin modify V-ATPase activity through other cellular targets. We next found that the AKT Ser/Thr kinase (AKT) inhibitor MK2206 blocks the starvation-dependent increase in lysosomal V-ATPase activity without altering basal activity. Expression of AKT1 or AKT3, but not AKT2, was required for increased lysosomal V-ATPase activity in response to amino acid starvation in mouse fibroblasts. Finally, HEK293T cells expressing only AKT1 responded normally to starvation, whereas cells expressing only AKT2 displayed a significantly reduced increase in V-ATPase activity and assembly upon starvation. These results show that AKT is required for controlling the rapid response of lysosomal V-ATPase activity to changes in amino acid availability and that this response depends on specific AKT isoforms.

  • AKT Ser/Thr kinase increases V-ATPase–dependent lysosomal acidification in response to amino acid starvation in mammalian cells
    The Journal of biological chemistry, 2020
    Co-Authors: Michael Collins, Laura A Stransky, Michael Forgac
    Abstract:

    The vacuolar H+-ATPase (V-ATPase) is an ATP-dependent proton pump that is essential for cellular homeostasis. V-ATPase activity is controlled by the regulated assembly of the enzyme from its component V1 and V0 domains. We previously reported that amino acid starvation rapidly increases V-ATPase assembly and activity in mammalian lysosomes, but the signaling pathways controlling this effect are unknown. In testing inhibitors of pathways important for controlling cellular metabolism, we found here that the cAMP-dependent protein kinase (PKA) inhibitor H89 increases lysosomal V-ATPase activity and blocks any further change upon starvation. The AMP-activated protein kinase (AMPK) inhibitor dorsomorphin decreased lysosomal V-ATPase activity and also blocked any increase upon starvation. However, CRISPR-mediated gene editing revealed that PKA and AMPK are not required for the starvation-dependent increase in lysosomal V-ATPase activity, indicating that H89 and dorsomorphin modify V-ATPase activity through other cellular targets. We next found that the AKT Ser/Thr kinase (AKT) inhibitor MK2206 blocks the starvation-dependent increase in lysosomal V-ATPase activity without altering basal activity. Expression of AKT1 or AKT3, but not AKT2, was required for increased lysosomal V-ATPase activity in response to amino acid starvation in mouse fibroblasts. Finally, HEK293T cells expressing only AKT1 responded normally to starvation, whereas cells expressing only AKT2 displayed a significantly reduced increase in V-ATPase activity and assembly upon starvation. These results show that AKT is required for controlling the rapid response of lysosomal V-ATPase activity to changes in amino acid availability and that this response depends on specific AKT isoforms.

Alex Toker – One of the best experts on this subject based on the ideXlab platform.

  • Abstract 4421: PTEN-deficient tumors depend on AKT2 for maintenance
    Molecular and Cellular Biology, 2014
    Co-Authors: Rebecca Chin, Steve P. Balk, Alex Toker
    Abstract:

    PTEN deficiency is frequently found in solid tumors. Since PTEN is yet to be effectively targeted with drugs, its downstream target Akt may provide more viable therapeutic strategies. The essential role of Akt in PTEN-null tumor initiation has been demonstrated in a number of studies. However, the role of Akt in the maintenance of established PTEN-deficient tumors is not known. Moreover, whether PTEN-null tumors depend on a specific Akt isoform for survival signaling remains elusive. In this study, we have developed a tet-on inducible system for expressing Akt1/2/3 shRNAs to determine the role of Akt isoforms in PTEN-deficient cancer progression. Three-dimensional (3D) matrigel cultures are employed to better recapitulate tumors growing in vivo. Administration of doxycycline (dox) in Akt1 or AKT2 shRNA PTEN-null prostate tumor cells at the start of culture resulted in the inhibition of spheroid formation, suggesting an important role of both Akt1 and AKT2 in the initial growth of spheroids. Conversely, when spheroids were allowed to form for 7 days, followed by dox for further 10 days, no difference was observed between Akt1-depleted and control spheroids. In contrast, silencing of AKT2 resulted in complete disintegration of spheroids. Confocal microscopy studies show a significant induction of active caspase-3 and fragmented nuclei in AKT2-silenced cells. Moreover, whereas Akt1 is uniformly expressed, AKT2 is localized in the cytoplasm and/or on the plasma membrane. Interestingly, the differences of effect of Akt isoforms on cell survival in conventional 2D culture are considerably more modest. The exclusive requirement of AKT2 for survival is also observed in other PTEN-deficient solid tumors, including breast cancer and glioblastoma. Importantly, shRNA silencing of AKT2 but not Akt1 promotes regression of prostate cancer xenografts. Mechanistically, we show that AKT2 silencing up-regulates p21 and the pro-apoptotic protein Bax and downregulates the insulin-like growth factor receptor-1. We also show that p21 is an effector of AKT2 in mediating prostate tumor cell survival. These results indicate that AKT2, but not Akt1, plays a critical role in PTEN-deficient tumor maintenance, and provide a rationale for developing therapeutics targeting AKT2. Current efforts are aimed at identifying novel Akt isoform-specific substrates that contribute to cancer progression using a genome-wide proteomic screen. The results of these studies could point to new targets for anti-cancer therapeutics. This work was supported by grants from NIH (A.T., CA092644; R.C., K99CA157945, T32 CA081156-09; S.B., P01 CA163227), the Department of Defense (S.B., W81XWH-09-1-0435) and a sponsored research grant from ImClone/Eli Lilly Inc. (A.T and R.C.). Citation Format: Rebecca Chin, Steve P. Balk, Alex Toker. PTEN-deficient tumors depend on AKT2 for maintenance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4421. doi:10.1158/1538-7445.AM2014-4421

  • PTEN-Deficient Tumors Depend on AKT2 for Maintenance and Survival
    Cancer discovery, 2014
    Co-Authors: Y. Rebecca Chin, Steve P. Balk, Xin Yuan, Alex Toker
    Abstract:

    Loss of PTEN is a common event in many cancers and leads to hyperactivation of the PI 3-K/Akt signaling pathway. The mechanisms by which Akt isoforms mediate signaling to phenotypes associated with PTEN-inactivation in cancer have not been defined. Here we show that AKT2 is exclusively required for PTEN-deficient prostate tumor spheroid maintenance whereas Akt1 is dispensable. shRNA silencing of AKT2 but not Akt1 promotes regression of prostate cancer xenografts. Mechanistically, we show that AKT2 silencing up-regulates p21 and the pro-apoptotic protein Bax and downregulates the insulin-like growth factor receptor-1. We also show that p21 is an effector of AKT2 in mediating prostate tumor maintenance. Moreover, AKT2 is also exclusively required for the maintenance and survival of other PTEN-deficient solid tumors, including breast cancer and glioblastoma. These findings identify a specific function for AKT2 in mediating survival of PTEN-deficient tumors and provide a rationale for developing therapeutics targeting AKT2.

  • Abstract 4090: AKT2-specific signaling in prostate cancer maintenance.
    Molecular and Cellular Biology, 2013
    Co-Authors: Yuet Ming Rebecca Chin, Steve P. Balk, Alex Toker
    Abstract:

    Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Mutations and amplification in genes regulating the PI 3-K/Akt pathway are common in prostate cancer, with deletion or mutations of PTEN being the most frequent. This has led to major efforts in developing anti-cancer drugs targeting the Akt pathway. Although the role of Akt in tumorigenesis has been studied extensively, little is known regarding isoform-specificity, and it is largely assumed that Akt isoforms play redundant roles in regulating cancer cell survival. In this study, we have developed a tet-on inducible system for expressing Akt1/2/3 shRNAs to determine the role of Akt isoforms in prostate cancer progression. Three-dimensional (3D) matrigel cultures are employed to better recapitulate tumors growing in vivo. Administration of doxycycline (dox) in Akt1 or AKT2 shRNA PTEN-deficient LNCaP cells at the start of culture resulted in the inhibition of spheroid formation, suggesting an important role of both Akt1 and AKT2 in the initial growth of spheroids. Conversely, when spheroids were allowed to form for 7 days, followed by dox for further 10 days, no difference was observed between Akt1-depleted and control spheroids. In contrast, silencing of AKT2 resulted in complete disintegration of spheroids. Confocal microscopy studies showed a significant induction of active caspase-3 and fragmented nuclei in AKT2-silenced cells. Moreover, whereas Akt1 is uniformly expressed, AKT2 is localized in the cytoplasm and/or on the plasma membrane. Interestingly, the differences of effect of Akt isoforms on cell survival in conventional 2D culture are considerably more modest. The exclusive requirement of AKT2 for survival is also observed in PC3 prostate cancer cells, which are also PTEN-deficient. Importantly, our preliminary data indicated that AKT2, but not Akt1 knockdown, led to tumor regression in the LnCaP xenograft model. These results indicate that AKT2, but not Akt1, plays a critical role in prostate cancer maintenance. Current efforts are aimed at identifying novel Akt isoform-specific substrates that contribute to prostate cancer progression using a genome-wide proteomic screen. The results of these studies could point to new targets for anti-cancer therapeutics. This work was supported by grants from NIH (A.T., CA122099; R.C., 1K99CA157945-01, T32 CA081156-09) Citation Format: Yuet Ming Rebecca Chin, Steve Balk, Alex Toker. AKT2-specific signaling in prostate cancer maintenance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4090. doi:10.1158/1538-7445.AM2013-4090

Philip N Tsichlis – One of the best experts on this subject based on the ideXlab platform.

  • The protein kinase Akt1 regulates the interferon response through phosphorylation of the transcriptional repressor EMSY.
    Proceedings of the National Academy of Sciences of the United States of America, 2012
    Co-Authors: Scott A Ezell, Christos Polytarchou, Maria Hatziapostolou, Ioannis Sanidas, Teeru Bihani, Michael J Comb, George Sourvinos, Philip N Tsichlis
    Abstract:

    The protein kinases Akt1, AKT2, and Akt3 possess nonredundant signaling properties, few of which have been investigated. Here, we present evidence for an Akt1-dependent pathway that controls interferon (IFN)-regulated gene expression and antiviral immunity. The target of this pathway is EMSY, an oncogenic interacting partner of BRCA2 that functions as a transcriptional repressor. Overexpression of EMSY in hTERT-immortalized mammary epithelial cells, and in breast and ovarian carcinoma cell lines, represses IFN-stimulated genes (ISGs) in a BRCA2-dependent manner, whereas its knockdown has the opposite effect. EMSY binds to the promoters of ISGs, suggesting that EMSY functions as a direct transcriptional repressor. Akt1, but not AKT2, phosphorylates EMSY at Ser209, relieving EMSY-mediated ISG repression. The Akt1/EMSY/ISG pathway is activated by both viral infection and IFN, and it inhibits the replication of HSV-1 and vesicular stomatitis virus (VSV). Collectively, these data define an Akt1-dependent pathway that contributes to the full activation of ISGs by relieving their repression by EMSY and BRCA2.

  • AKT2 regulates all akt isoforms and promotes resistance to hypoxia through induction of mir 21 upon oxygen deprivation
    Cancer Research, 2011
    Co-Authors: Christos Polytarchou, Maria Hatziapostolou, Ioanna G Maroulakou, Dimitrios Iliopoulos, Filippos Kottakis, Kevin Struhl, Philip N Tsichlis
    Abstract:

    The growth and survival of tumor cells in an unfavorable hypoxic environment depend upon their adaptibility. Here we show that both normal and tumor cells expressing the protein kinase AKT2 are more resistant to hypoxia than cells expressing Akt1 or Akt3. This is due to the differential regulation of miR-21, which is upregulated by hypoxia only in AKT2-expressing cells. By upregulating miR-21 upon oxygen deprivation, AKT2 downregulates PTEN and activates all three Akt isoforms. MiR-21 also targets PDCD4 and Spry1, and the combined downregulation of these proteins with PTEN is sufficient to confer resistance to hypoxia. Furthermore, the miR-21 induction by AKT2 during hypoxia depends upon the binding of NF-κB, CREB and CBP/p300 to the miR-21 promoter, in addition to the regional acetylation of histone H3K9, all of which are under the control of AKT2. Analysis of the AKT2-miR-21 pathway in hypoxic MMTV-PyMT-induced mouse mammary adenocarcinomas and human ovarian carcinomas confirmed the activity of the pathway in vivo. Taken together, this study identifies a novel AKT2-dependent pathway that is activated by hypoxia and promotes tumor resistance via induction of miR-21.

  • micrornas differentially regulated by akt isoforms control emt and stem cell renewal in cancer cells
    Science Signaling, 2009
    Co-Authors: Dimitrios Iliopoulos, Christos Polytarchou, Maria Hatziapostolou, Ioanna G Maroulakou, Filippos Kottakis, Kevin Struhl, Philip N Tsichlis
    Abstract:

    Although Akt is known to play a role in human cancer, the relative contribution of its three isoforms to oncogenesis remains to be determined. We expressed each isoform individually in an Akt1 −/− / AKT2 −/− / Akt3 −/− cell line. MicroRNA profiling of growth factor–stimulated cells revealed unique microRNA signatures for cells with each isoform. Among the differentially regulated microRNAs, the abundance of the miR-200 family was decreased in cells bearing AKT2. Knockdown of Akt1 in transforming growgrowth factor–β (TGFβ)–treated MCF10A cells also decreased the abundance of miR-200; however, knockdown of AKT2, or of both Akt1 and AKT2, did not. Furthermore, Akt1 knockdown in MCF10A cells promoted TGFβ-induced epithelial-mesemesenchymalnsition (EMT) and a stem cell–like phenotype. Carcinomas developing in MMTV-cErbB2/ Akt1 −/− mice showed increased invasiveness because of miR-200 down-regulation. Finally, the ratio of Akt1 to AKT2 and the abundance of miR-200 and of the messenger RNA encoding E-cadherin in a set of primary and metastatic human breast cancers were consistent with the hypothesis that in many cases breast cancer metastasis may be under the control of the Akt–miR-200–E-cadherin axis. We conclude that induction of EMT is controlled by microRNAs whose abundance depends on the balance between Akt1 and AKT2 rather than on the overall activity of Akt.