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Book ; Thesis: Analysis of 3-phosphoinositide dependent kinase 1 signaling and function in murine embryonic stem cells

Tamgüney, Tanja

2008

Author's details	vorgelegt von Tanja Tamgüney
Language	English
Size	106 Bl., Ill., graph. Darst., 30 cm
Publishing country	Germany
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Erlangen, Nürnberg, Univ., Diss., 2008 (Nicht für den Austausch)
HBZ-ID	HT015754557
Database	Catalogue ZB MED Medicine, Health

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2008 E 1759	order for loan	Magazin

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Book ; Online ; Thesis: Analysis of 3-phosphoinositide dependent kinase 1 signaling and function in murine embryonic stem cells

Tamgüney, Tanja [Verfasser]

2008

Author's details	vorgelegt von Tanja Tamgüney
Keywords	Biowissenschaften, Biologie ; Life Science, Biology
Subject code	sg570
Language	English
Document type	Book ; Online ; Thesis
Database	Digital theses on the web

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Article: New insights into PTEN.

Tamguney, Tanja / Stokoe, David

Journal of cell science

2007 Volume 120, Issue Pt 23, Page(s) 4071–4079

Abstract: The functions ascribed to PTEN have become more diverse since its discovery as a putative phosphatase mutated in many human tumors. Although it can dephosphorylate lipids and proteins, it also has functions independent of phosphatase activity in normal ... ...

Abstract	The functions ascribed to PTEN have become more diverse since its discovery as a putative phosphatase mutated in many human tumors. Although it can dephosphorylate lipids and proteins, it also has functions independent of phosphatase activity in normal and pathological states. In addition, control of PTEN function is very complex. It is positively and negatively regulated at the transcriptional level, as well as post-translationally by phosphorylation, ubiquitylation, oxidation and acetylation. Although most of its tumor suppressor activity is likely to be caused by lipid dephosphorylation at the plasma membrane, PTEN also resides in the cytoplasm and nucleus, and its subcellular distribution is under strict control. Deregulation of PTEN function is implicated in other human diseases in addition to cancer, including diabetes and autism.
MeSH term(s)	Diabetes Mellitus/genetics ; Diabetes Mellitus/metabolism ; Diabetes Mellitus/pathology ; Gene Expression Regulation ; Humans ; Models, Biological ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; PTEN Phosphohydrolase/metabolism ; PTEN Phosphohydrolase/physiology ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoric Monoester Hydrolases/metabolism ; Phosphoric Monoester Hydrolases/physiology ; Protein Processing, Post-Translational ; Transcription, Genetic ; Tumor Suppressor Proteins
Chemical Substances	Tumor Suppressor Proteins ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67)
Language	English
Publishing date	2007-12-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.015230
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Article: New insights into PTEN

Tamguney, Tanja / Stokoe, David

Journal of cell science. 2007 Dec. 1, v. 120, no. 23

2007

Abstract	The functions ascribed to PTEN have become more diverse since its discovery as a putative phosphatase mutated in many human tumors. Although it can dephosphorylate lipids and proteins, it also has functions independent of phosphatase activity in normal and pathological states. In addition, control of PTEN function is very complex. It is positively and negatively regulated at the transcriptional level, as well as post-translationally by phosphorylation, ubiquitylation, oxidation and acetylation. Although most of its tumor suppressor activity is likely to be caused by lipid dephosphorylation at the plasma membrane, PTEN also resides in the cytoplasm and nucleus, and its subcellular distribution is under strict control. Deregulation of PTEN function is implicated in other human diseases in addition to cancer, including diabetes and autism.
Language	English
Dates of publication	2007-1201
Size	p. 4071-4079.
Publishing place	The Company of Biologists Limited
Document type	Article
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Analysis of 3-phosphoinositide-dependent kinase-1 signaling and function in ES cells.

Tamgüney, Tanja / Zhang, Chao / Fiedler, Dorothea / Shokat, Kevan / Stokoe, David

Experimental cell research

2008 Volume 314, Issue 11-12, Page(s) 2299–2312

Abstract: 3-phosphoinositide-dependent kinase-1 (PDK1) phosphorylates and activates several kinases in the cAMP-dependent, cGMP-dependent and protein kinase C (AGC) family. Many putative PDK1 substrates have been identified, but have not been analyzed following ... ...

Abstract	3-phosphoinositide-dependent kinase-1 (PDK1) phosphorylates and activates several kinases in the cAMP-dependent, cGMP-dependent and protein kinase C (AGC) family. Many putative PDK1 substrates have been identified, but have not been analyzed following transient and specific inhibition of PDK1 activity. Here, we demonstrate that a previously characterized PDK1 inhibitor, BX-795, shows biological effects that are not consistent with PDK1 inhibition. Therefore, we describe the creation and characterization of a PDK1 mutant, L159G, which can bind inhibitor analogues containing bulky groups that hinder access to the ATP binding pocket of wild type (WT) kinases. When expressed in PDK1(-/-) ES cells, PDK1 L159G restored phosphorylation of PDK1 targets known to be hypophosphorylated in these cells. Screening of multiple inhibitor analogues showed that 1-NM-PP1 and 3,4-DMB-PP1 optimally inhibited the phosphorylation of PDK1 targets in PDK1(-/-) ES cells expressing PDK1 L159G but not WT PDK1. These compounds confirmed previously assumed PDK1 substrates, but revealed distinct dephosphorylation kinetics. While PDK1 inhibition had little effect on cell growth, it sensitized cells to apoptotic stimuli. Furthermore, PDK1 loss abolished growth of allograft tumors. Taken together we describe a model system that allows for acute and reversible inhibition of PDK1 in cells, to probe biochemical and biological consequences.
MeSH term(s)	3-Phosphoinositide-Dependent Protein Kinases ; Animals ; Cell Cycle/physiology ; Cells, Cultured ; Embryonic Stem Cells/cytology ; Embryonic Stem Cells/physiology ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Female ; Humans ; Mice ; Mice, Knockout ; Mice, Nude ; Molecular Structure ; Phosphorylation ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Pyrazoles/chemistry ; Pyrazoles/metabolism ; Pyrimidines/chemistry ; Pyrimidines/metabolism ; Signal Transduction/physiology ; Transplantation, Homologous
Chemical Substances	4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine ; Enzyme Inhibitors ; Pyrazoles ; Pyrimidines ; 3-Phosphoinositide-Dependent Protein Kinases (EC 2.7.11.1) ; PDPK1 protein, human (EC 2.7.11.1) ; Pdpk1 protein, mouse (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2008-04-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/j.yexcr.2008.04.006
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway.

Nan, Xiaolin / Tamgüney, Tanja M / Collisson, Eric A / Lin, Li-Jung / Pitt, Cameron / Galeas, Jacqueline / Lewis, Sophia / Gray, Joe W / McCormick, Frank / Chu, Steven

Proceedings of the National Academy of Sciences of the United States of America

2015 Volume 112, Issue 26, Page(s) 7996–8001

Abstract: Rat sarcoma (Ras) GTPases regulate cell proliferation and survival through effector pathways including Raf-MAPK, and are the most frequently mutated genes in human cancer. Although it is well established that Ras activity requires binding to both GTP and ...

Abstract	Rat sarcoma (Ras) GTPases regulate cell proliferation and survival through effector pathways including Raf-MAPK, and are the most frequently mutated genes in human cancer. Although it is well established that Ras activity requires binding to both GTP and the membrane, details of how Ras operates on the cell membrane to activate its effectors remain elusive. Efforts to target mutant Ras in human cancers to therapeutic benefit have also been largely unsuccessful. Here we show that Ras-GTP forms dimers to activate MAPK. We used quantitative photoactivated localization microscopy (PALM) to analyze the nanoscale spatial organization of PAmCherry1-tagged KRas 4B (hereafter referred to KRas) on the cell membrane under various signaling conditions. We found that at endogenous expression levels KRas forms dimers, and KRas(G12D), a mutant that constitutively binds GTP, activates MAPK. Overexpression of KRas leads to formation of higher order Ras nanoclusters. Conversely, at lower expression levels, KRas(G12D) is monomeric and activates MAPK only when artificially dimerized. Moreover, dimerization and signaling of KRas are both dependent on an intact CAAX (C, cysteine; A, aliphatic; X, any amino acid) motif that is also known to mediate membrane localization. These results reveal a new, dimerization-dependent signaling mechanism of Ras, and suggest Ras dimers as a potential therapeutic target in mutant Ras-driven tumors.
MeSH term(s)	Animals ; Cell Line ; Cricetinae ; Dimerization ; Enzyme Activation ; Guanosine Triphosphate/metabolism ; MAP Kinase Signaling System ; Mitogen-Activated Protein Kinases/metabolism ; ras Proteins/metabolism
Chemical Substances	Guanosine Triphosphate (86-01-1) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2015-06-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1509123112
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Article: Translational deregulation in PDK-1-/- embryonic stem cells.

Tominaga, Yuichi / Tamgüney, Tanja / Kolesnichenko, Marina / Bilanges, Benoit / Stokoe, David

Molecular and cellular biology

2005 Volume 25, Issue 19, Page(s) 8465–8475

Abstract: PDK-1 is a protein kinase that is critical for the activation of many downstream protein kinases in the AGC superfamily, through phosphorylation of the activation loop site on these substrates. Cells lacking PDK-1 show decreased activity of these protein ...

Abstract	PDK-1 is a protein kinase that is critical for the activation of many downstream protein kinases in the AGC superfamily, through phosphorylation of the activation loop site on these substrates. Cells lacking PDK-1 show decreased activity of these protein kinases, including protein kinase B (PKB) and p70S6K, whereas mTOR activity remains largely unaffected. Here we show, by assessing both association of cellular RNAs with polysomes and by metabolic labeling, that PDK-1-/- embryonic stem (ES) cells exhibit defects in mRNA translation. We identify which mRNAs are most dramatically translationally regulated in cells lacking PDK-1 expression by performing microarray analysis of total and polysomal RNA in these cells. In addition to the decreased translation of many RNAs, a smaller number of RNAs show increased association with polyribosomes in PDK-1-/- ES cells relative to PDK-1+/+ ES cells. We show that PKB activity is a critical downstream component of PDK-1 in mediating translation of cystatin C, RANKL, and Rab11a, whereas mTOR activity is less important for effective translation of these targets.
MeSH term(s)	3-Phosphoinositide-Dependent Protein Kinases ; Animals ; Blotting, Western ; Carrier Proteins/metabolism ; Cystatin C ; Cystatins/metabolism ; Electrophoresis, Polyacrylamide Gel ; Embryo, Mammalian/cytology ; Enzyme Activation ; Gene Expression Regulation, Developmental ; Humans ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Transgenic ; Oligonucleotide Array Sequence Analysis ; Phosphorylation ; Polyribosomes/metabolism ; Protein Biosynthesis ; Protein Kinases/metabolism ; Protein-Serine-Threonine Kinases/genetics ; RANK Ligand ; RNA/chemistry ; RNA/metabolism ; RNA, Messenger/metabolism ; Receptor Activator of Nuclear Factor-kappa B ; Reverse Transcriptase Polymerase Chain Reaction ; Ribosomal Protein S6 Kinases, 70-kDa/metabolism ; Ribosomes/metabolism ; Stem Cells/cytology ; Sucrose/pharmacology ; TOR Serine-Threonine Kinases ; Time Factors ; rab GTP-Binding Proteins/metabolism
Chemical Substances	CST3 protein, human ; Carrier Proteins ; Cst3 protein, mouse ; Cystatin C ; Cystatins ; Membrane Glycoproteins ; RANK Ligand ; RNA, Messenger ; Receptor Activator of Nuclear Factor-kappa B ; TNFRSF11A protein, human ; TNFSF11 protein, human ; Tnfrsf11a protein, mouse ; Tnfsf11 protein, mouse ; Sucrose (57-50-1) ; RNA (63231-63-0) ; Protein Kinases (EC 2.7.-) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; mTOR protein, mouse (EC 2.7.1.1) ; 3-Phosphoinositide-Dependent Protein Kinases (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Ribosomal Protein S6 Kinases, 70-kDa (EC 2.7.11.1) ; rab11 protein (EC 3.6.1.-) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2005-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	779397-2
ISSN	1098-5549 ; 0270-7306
ISSN (online)	1098-5549
ISSN	0270-7306
DOI	10.1128/MCB.25.19.8465-8475.2005
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Article ; Online: Single-molecule superresolution imaging allows quantitative analysis of RAF multimer formation and signaling.

Nan, Xiaolin / Collisson, Eric A / Lewis, Sophia / Huang, Jing / Tamgüney, Tanja M / Liphardt, Jan T / McCormick, Frank / Gray, Joe W / Chu, Steven

Proceedings of the National Academy of Sciences of the United States of America

2013 Volume 110, Issue 46, Page(s) 18519–18524

Abstract: The RAF serine/threonine kinases regulate cell growth through the MAPK pathway, and are targeted by small-molecule RAF inhibitors (RAFis) in human cancer. It is now apparent that protein multimers play an important role in RAF activation and tumor ... ...

Abstract	The RAF serine/threonine kinases regulate cell growth through the MAPK pathway, and are targeted by small-molecule RAF inhibitors (RAFis) in human cancer. It is now apparent that protein multimers play an important role in RAF activation and tumor response to RAFis. However, the exact stoichiometry and cellular location of these multimers remain unclear because of the lack of technologies to visualize them. In the present work, we demonstrate that photoactivated localization microscopy (PALM), in combination with quantitative spatial analysis, provides sufficient resolution to directly visualize protein multimers in cells. Quantitative PALM imaging showed that CRAF exists predominantly as cytoplasmic monomers under resting conditions but forms dimers as well as trimers and tetramers at the cell membrane in the presence of active RAS. In contrast, N-terminal truncated CRAF (CatC) lacking autoinhibitory domains forms constitutive dimers and occasional tetramers in the cytoplasm, whereas a CatC mutant with a disrupted CRAF-CRAF dimer interface does not. Finally, artificially forcing CRAF to the membrane by fusion to a RAS CAAX motif induces multimer formation but activates RAF/MAPK only if the dimer interface is intact. Together, these quantitative results directly confirm the existence of RAF dimers and potentially higher-order multimers and their involvement in cell signaling, and showed that RAF multimer formation can result from multiple mechanisms and is a critical but not sufficient step for RAF activation.
MeSH term(s)	Animals ; Carcinogenesis/chemistry ; Cell Line ; Cricetinae ; Enzyme Activation/physiology ; Microscopy/methods ; Molecular Imaging/methods ; Protein Multimerization/physiology ; Signal Transduction/physiology ; raf Kinases/chemistry ; ras Proteins/metabolism
Chemical Substances	raf Kinases (EC 2.7.11.1) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2013-10-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1318188110
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Article: Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma.

Wiencke, John K / Zheng, Shichun / Jelluma, Nanette / Tihan, Tarik / Vandenberg, Scott / Tamgüney, Tanja / Baumber, Rachel / Parsons, Ramon / Lamborn, Kathleen R / Berger, Mitchel S / Wrensch, Margaret R / Haas-Kogan, Daphne Adele / Stokoe, David

Neuro-oncology

2007 Volume 9, Issue 3, Page(s) 271–279

Abstract: Glioblastoma multiforme (GBM) can present as either de novo or secondary tumors arising from previously diagnosed low-grade gliomas. Although these tumor types are phenotypically indistinguishable, de novo and secondary GBMs are associated with distinct ... ...

Abstract	Glioblastoma multiforme (GBM) can present as either de novo or secondary tumors arising from previously diagnosed low-grade gliomas. Although these tumor types are phenotypically indistinguishable, de novo and secondary GBMs are associated with distinct genetic characteristics. PTEN mutations, which result in activation of the phosphoinositide 3-kinase (PI3K) signal transduction pathway, are frequent in de novo but not in secondary GBMs or their antecedent low-grade tumors. Results we present here show that grade II astrocytomas, oligodendrogliomas, and oligoastrocytomas commonly display methylation of the PTEN promoter, a finding that is absent in nontumor brain specimens and rare in de novo GBMs. Methylation of the PTEN promoter correlates with protein kinase B (PKB/Akt) phosphorylation, reflecting functional activation of the PI3K pathway. Our results also demonstrate frequent methylation of the PTEN promoter in grade III astrocytomas and secondary GBMs, consistent with the hypothesis that these tumors arise from lower grade precursors. PTEN methylation is rare in de novo GBMs and is mutually exclusive with PTEN mutations. We conclude that methylation of the PTEN promoter may represent an alternate mechanism by which PI3K signaling is increased in grade II and III gliomas as well as secondary GBMs, a finding that offers new therapeutic approaches in these patients.
MeSH term(s)	Adult ; Biomarkers, Tumor ; Blotting, Western ; Brain Neoplasms/genetics ; DNA Methylation ; Genetic Markers ; Glioblastoma/genetics ; Glioblastoma/secondary ; Glioma/genetics ; Humans ; Middle Aged ; PTEN Phosphohydrolase/genetics ; PTEN Phosphohydrolase/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Polymerase Chain Reaction ; Promoter Regions, Genetic
Chemical Substances	Biomarkers, Tumor ; Genetic Markers ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67)
Language	English
Publishing date	2007-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1215/15228517-2007-003
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Article ; Online: Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis.

De Semir, David / Nosrati, Mehdi / Bezrookove, Vladimir / Dar, Altaf A / Federman, Scot / Bienvenu, Geraldine / Venna, Suraj / Rangel, Javier / Climent, Joan / Meyer Tamgüney, Tanja M / Thummala, Suresh / Tong, Schuyler / Leong, Stanley P L / Haqq, Chris / Billings, Paul / Miller, James R / Sagebiel, Richard W / Debs, Robert / Kashani-Sabet, Mohammed

Proceedings of the National Academy of Sciences of the United States of America

2012 Volume 109, Issue 18, Page(s) 7067–7072

Abstract: Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wild-type BRAF. Here, we show that the activation of Pleckstrin homology ... ...

Abstract	Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wild-type BRAF. Here, we show that the activation of Pleckstrin homology domain-interacting protein (PHIP), promotes melanoma metastasis, can be used to classify a subset of primary melanomas, and is a prognostic biomarker for melanoma. Systemic, plasmid-based shRNA targeting of Phip inhibited the metastatic progression of melanoma, whereas stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged the survival of tumor-bearing mice. The human PHIP gene resides on 6q14.1, and although 6q loss has been observed in melanoma, the PHIP locus was preserved in melanoma cell lines and patient samples, and its overexpression was an independent adverse predictor of survival in melanoma patients. In addition, a high proportion of PHIP-overexpressing melanomas harbored increased PHIP copy number. PHIP-overexpressing melanomas include tumors with wild-type BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog, and phosphatase and tensin homolog, demonstrating PHIP activation in triple-negative melanoma. These results describe previously unreported roles for PHIP in predicting and promoting melanoma metastasis, and in the molecular classification of melanoma.
MeSH term(s)	Animals ; Base Sequence ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Cell Line, Tumor ; Female ; Humans ; Intracellular Signaling Peptides and Proteins/antagonists & inhibitors ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/secondary ; Melanoma, Experimental/genetics ; Melanoma, Experimental/metabolism ; Melanoma, Experimental/secondary ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Nerve Tissue Proteins/antagonists & inhibitors ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; RNA, Small Interfering/genetics ; Signal Transduction
Chemical Substances	Biomarkers, Tumor ; Intracellular Signaling Peptides and Proteins ; Nerve Tissue Proteins ; PHIP protein, human ; Phip protein, mouse ; RNA, Small Interfering
Language	English
Publishing date	2012-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1119949109
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