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Article ; Online: MRAS: A Close but Understudied Member of the RAS Family.

Young, Lucy C / Rodriguez-Viciana, Pablo

Cold Spring Harbor perspectives in medicine

2018 Volume 8, Issue 12

Abstract: MRAS is the closest relative to the classical RAS oncoproteins and shares most regulatory and effector interactions. However, it also has unique functions, including its ability to function as a phosphatase regulatory subunit when in complex with SHOC2 ... ...

Abstract	MRAS is the closest relative to the classical RAS oncoproteins and shares most regulatory and effector interactions. However, it also has unique functions, including its ability to function as a phosphatase regulatory subunit when in complex with SHOC2 and protein phosphatase 1 (PP1). This phosphatase complex regulates a crucial step in the activation cycle of RAF kinases and provides a key coordinate input required for efficient ERK pathway activation and transformation by RAS. MRAS mutations rarely occur in cancer but deregulated expression may play a role in tumorigenesis in some settings. Activating mutations in MRAS (as well as SHOC2 and PP1) do occur in the RASopathy Noonan syndrome, underscoring a key role for MRAS within the RAS-ERK pathway. MRAS also has unique roles in cell migration and differentiation and has properties consistent with a key role in the regulation of cell polarity. Further investigations should shed light on what remains a relatively understudied RAS family member.
MeSH term(s)	Carcinogenesis/genetics ; Cell Differentiation/genetics ; Cell Movement/genetics ; Cell Polarity/genetics ; Gene Expression Regulation ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; MAP Kinase Signaling System/genetics ; Noonan Syndrome/genetics ; Protein Phosphatase 1/metabolism ; Signal Transduction ; ras Proteins/genetics ; ras Proteins/metabolism
Chemical Substances	Intracellular Signaling Peptides and Proteins ; MRAS protein, human ; SHOC2 protein, human ; Protein Phosphatase 1 (EC 3.1.3.16) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2018-12-03
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a033621
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Article ; Online: Structure of the SHOC2-MRAS-PP1C complex provides insights into RAF activation and Noonan syndrome.

Bonsor, Daniel A / Alexander, Patrick / Snead, Kelly / Hartig, Nicole / Drew, Matthew / Messing, Simon / Finci, Lorenzo I / Nissley, Dwight V / McCormick, Frank / Esposito, Dominic / Rodriguez-Viciana, Pablo / Stephen, Andrew G / Simanshu, Dhirendra K

Nature structural & molecular biology

2022 Volume 29, Issue 10, Page(s) 966–977

Abstract: SHOC2 acts as a strong synthetic lethal interactor with MEK inhibitors in multiple KRAS cancer cell lines. SHOC2 forms a heterotrimeric complex with MRAS and PP1C that is essential for regulating RAF and MAPK-pathway activation by dephosphorylating a ... ...

Abstract	SHOC2 acts as a strong synthetic lethal interactor with MEK inhibitors in multiple KRAS cancer cell lines. SHOC2 forms a heterotrimeric complex with MRAS and PP1C that is essential for regulating RAF and MAPK-pathway activation by dephosphorylating a specific phosphoserine on RAF kinases. Here we present the high-resolution crystal structure of the SHOC2-MRAS-PP1C (SMP) complex and apo-SHOC2. Our structures reveal that SHOC2, MRAS, and PP1C form a stable ternary complex in which all three proteins synergistically interact with each other. Our results show that dephosphorylation of RAF substrates by PP1C is enhanced upon interacting with SHOC2 and MRAS. The SMP complex forms only when MRAS is in an active state and is dependent on SHOC2 functioning as a scaffolding protein in the complex by bringing PP1C and MRAS together. Our results provide structural insights into the role of the SMP complex in RAF activation and how mutations found in Noonan syndrome enhance complex formation, and reveal new avenues for therapeutic interventions.
MeSH term(s)	Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; MAP Kinase Signaling System/genetics ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Noonan Syndrome/genetics ; Noonan Syndrome/metabolism ; Phosphoserine/metabolism ; Protein Phosphatase 1 ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; raf Kinases/genetics ; raf Kinases/metabolism ; ras Proteins/metabolism
Chemical Substances	Intracellular Signaling Peptides and Proteins ; MRAS protein, human ; SHOC2 protein, human ; Phosphoserine (17885-08-4) ; raf Kinases (EC 2.7.11.1) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2) ; Protein Phosphatase 1 (EC 3.1.3.16) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2022-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/s41594-022-00841-4
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Article ; Online: Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex.

Roehrig, Anne E / Klupsch, Kristina / Oses-Prieto, Juan A / Chaib, Selim / Henderson, Stephen / Emmett, Warren / Young, Lucy C / Surinova, Silvia / Blees, Andreas / Pfeiffer, Anett / Tijani, Maha / Brunk, Fabian / Hartig, Nicole / Muñoz-Alegre, Marta / Hergovich, Alexander / Jennings, Barbara H / Burlingame, Alma L / Rodriguez-Viciana, Pablo

PloS one

2021 Volume 16, Issue 8, Page(s) e0254697

Abstract: The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of ... ...

Abstract	The PAF complex (PAFC) coordinates transcription elongation and mRNA processing and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions both at the cell cortex and nucleus and is a key mediator of contact inhibition but the molecular mechanisms remain unclear. In this study we have used affinity proteomics to identify novel Merlin interacting proteins and show that Merlin forms a complex with multiple proteins involved in RNA processing including the PAFC and the CHD1 chromatin remodeller. Tumour-derived inactivating mutations in both Merlin and the CDC73 PAFC subunit mutually disrupt their interaction and growth suppression by Merlin requires CDC73. Merlin interacts with the PAFC in a cell density-dependent manner and we identify a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, Merlin is part of a tumour suppressor network regulated by cell-cell adhesion which coordinates post-initiation steps of the transcription cycle of genes mediating contact inhibition.
MeSH term(s)	Cell Adhesion/genetics ; Cell Proliferation/genetics ; Chromatin/genetics ; Chromatin Assembly and Disassembly/genetics ; Contact Inhibition/genetics ; DNA Helicases/genetics ; DNA-Binding Proteins/genetics ; Gene Expression Regulation/genetics ; HEK293 Cells ; Humans ; Neoplasms/genetics ; Neoplasms/pathology ; Neurofibromin 2/genetics ; Protein Binding/genetics ; Protein Interaction Maps/genetics ; Signal Transduction/genetics ; Tumor Suppressor Proteins/genetics
Chemical Substances	CDC73 protein, human ; Chromatin ; DNA-Binding Proteins ; Neurofibromin 2 ; Tumor Suppressor Proteins ; DNA Helicases (EC 3.6.4.-) ; CHD1 protein, human (EC 3.6.4.12)
Language	English
Publishing date	2021-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0254697
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Article ; Online: SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics.

Boned Del Río, Isabel / Young, Lucy C / Sari, Sibel / Jones, Greg G / Ringham-Terry, Benjamin / Hartig, Nicole / Rejnowicz, Ewa / Lei, Winnie / Bhamra, Amandeep / Surinova, Silvia / Rodriguez-Viciana, Pablo

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

2019 Volume 116, Issue 27, Page(s) 13330–13339

Abstract: Despite the crucial role of RAF kinases in cell signaling and disease, we still lack a complete understanding of their regulation. Heterodimerization of RAF kinases as well as dephosphorylation of a conserved "S259" inhibitory site are important steps ... ...

Abstract	Despite the crucial role of RAF kinases in cell signaling and disease, we still lack a complete understanding of their regulation. Heterodimerization of RAF kinases as well as dephosphorylation of a conserved "S259" inhibitory site are important steps for RAF activation but the precise mechanisms and dynamics remain unclear. A ternary complex comprised of SHOC2, MRAS, and PP1 (SHOC2 complex) functions as a RAF S259 holophosphatase and gain-of-function mutations in SHOC2, MRAS, and PP1 that promote complex formation are found in Noonan syndrome. Here we show that SHOC2 complex-mediated S259 RAF dephosphorylation is critically required for growth factor-induced RAF heterodimerization as well as for MEK dissociation from BRAF. We also uncover SHOC2-independent mechanisms of RAF and ERK pathway activation that rely on N-region phosphorylation of CRAF. In DLD-1 cells stimulated with EGF, SHOC2 function is essential for a rapid transient phase of ERK activation, but is not required for a slow, sustained phase that is instead driven by palmitoylated H/N-RAS proteins and CRAF. Whereas redundant SHOC2-dependent and -independent mechanisms of RAF and ERK activation make SHOC2 dispensable for proliferation in 2D, KRAS mutant cells preferentially rely on SHOC2 for ERK signaling under anchorage-independent conditions. Our study highlights a context-dependent contribution of SHOC2 to ERK pathway dynamics that is preferentially engaged by KRAS oncogenic signaling and provides a biochemical framework for selective ERK pathway inhibition by targeting the SHOC2 holophosphatase.
MeSH term(s)	CRISPR-Associated Protein 9 ; CRISPR-Cas Systems ; Cell Line, Tumor ; Gene Editing ; Gene Knockout Techniques ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; MAP Kinase Signaling System ; Phosphorylation ; Protein Multimerization ; raf Kinases/chemistry ; raf Kinases/metabolism ; ras Proteins/metabolism
Chemical Substances	Intracellular Signaling Peptides and Proteins ; MRAS protein, human ; SHOC2 protein, human ; raf Kinases (EC 2.7.11.1) ; CRISPR-Associated Protein 9 (EC 3.1.-) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2019-06-18
Publishing country	United States
Document type	Journal Article ; 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.1902658116
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Article: Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome.

Rodriguez-Viciana, Pablo / Rauen, Katherine A

Methods in enzymology

2008 Volume 438, Page(s) 277–289

Abstract: Cardio-facio-cutaneous syndrome (CFC) is a sporadic, complex developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, growth deficiency, hypotonia, and developmental delay. CFC is caused by ... ...

Abstract	Cardio-facio-cutaneous syndrome (CFC) is a sporadic, complex developmental disorder involving characteristic craniofacial features, cardiac defects, ectodermal abnormalities, growth deficiency, hypotonia, and developmental delay. CFC is caused by alteration of activity through the mitogen-activated protein kinase (MAPK) pathway due to heterogeneous de novo germline mutations in B-Raf mutant proteins, MEK1 and MEK2. Approximately 75% of individuals with CFC have mutations in BRAF. In vitro functional studies demonstrate that many of these mutations confer increase activity upon the mutant protein as compared to the wildtype protein. However, as is seen cancer, some of the B-Raf mutant proteins are kinase impaired. Western blot analyses corroborate kinase assays as determined by mutant proteins phosphorylating downstream effectors MEK and ERK. Approximately 25% of individuals with CFC have mutations in either MEK1 or MEK2 that lead to increased MEK kinase activity as judged by increased phosphorylation of its downstream effector ERK. Unlike BRAF, no somatic mutations have ever been identified in MEK genes. The identification of novel germline BRAF and MEK mutations in CFC will help understand the pathophysiology of this syndrome. Furthermore, it will also provide insight to the normal function of B-Raf and MEK, and contribute to the knowledge of the role of the MAPK pathway in cancer. Since the MAPK pathway has been studied intensively in the context of cancer, numerous therapeutics that specifically target this pathway may merit investigation in this population of patients.
MeSH term(s)	Amino Acid Substitution ; Blotting, Western ; Craniofacial Abnormalities/genetics ; Heart Defects, Congenital/genetics ; Humans ; MAP Kinase Kinase 1/genetics ; MAP Kinase Kinase 2/genetics ; Proto-Oncogene Proteins B-raf/genetics ; Skin Abnormalities/genetics ; Syndrome ; raf Kinases/analysis
Chemical Substances	MAP2K2 protein, human (EC 2.7.1.-) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; raf Kinases (EC 2.7.11.1) ; MAP Kinase Kinase 1 (EC 2.7.12.2) ; MAP Kinase Kinase 2 (EC 2.7.12.2) ; MAP2K1 protein, human (EC 2.7.12.2)
Language	English
Publishing date	2008
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	0076-6879
ISSN	0076-6879
DOI	10.1016/S0076-6879(07)38019-1
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Article ; Online: SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis.

Young, Lucy C / Hartig, Nicole / Boned Del Río, Isabel / Sari, Sibel / Ringham-Terry, Benjamin / Wainwright, Joshua R / Jones, Greg G / McCormick, Frank / Rodriguez-Viciana, Pablo

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

2018 Volume 115, Issue 45, Page(s) E10576–E10585

Abstract: Dephosphorylation of the inhibitory "S259" site on RAF kinases (S259 on CRAF, S365 on BRAF) plays a key role in RAF activation. The MRAS GTPase, a close relative of RAS oncoproteins, interacts with SHOC2 and protein phosphatase 1 (PP1) to form a ... ...

Abstract	Dephosphorylation of the inhibitory "S259" site on RAF kinases (S259 on CRAF, S365 on BRAF) plays a key role in RAF activation. The MRAS GTPase, a close relative of RAS oncoproteins, interacts with SHOC2 and protein phosphatase 1 (PP1) to form a heterotrimeric holoenzyme that dephosphorylates this S259 RAF site. MRAS and SHOC2 function as PP1 regulatory subunits providing the complex with striking specificity against RAF. MRAS also functions as a targeting subunit as membrane localization is required for efficient RAF dephosphorylation and ERK pathway regulation in cells. SHOC2's predicted structure shows remarkable similarities to the A subunit of PP2A, suggesting a case of convergent structural evolution with the PP2A heterotrimer. We have identified multiple regions in SHOC2 involved in complex formation as well as residues in MRAS switch I and the interswitch region that help account for MRAS's unique effector specificity for SHOC2-PP1. MRAS, SHOC2, and PPP1CB are mutated in Noonan syndrome, and we show that syndromic mutations invariably promote complex formation with each other, but not necessarily with other interactors. Thus, Noonan syndrome in individuals with SHOC2, MRAS, or PPPC1B mutations is likely driven at the biochemical level by enhanced ternary complex formation and highlights the crucial role of this phosphatase holoenzyme in RAF S259 dephosphorylation, ERK pathway dynamics, and normal human development.
MeSH term(s)	Carrier Proteins ; Cell Line ; HEK293 Cells ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; MAP Kinase Signaling System ; Models, Molecular ; Mutation ; Noonan Syndrome/genetics ; Noonan Syndrome/metabolism ; Phosphorylation ; Protein Phosphatase 1/genetics ; Protein Phosphatase 1/metabolism ; Sequence Alignment ; raf Kinases/metabolism ; ras Proteins/genetics ; ras Proteins/metabolism
Chemical Substances	Carrier Proteins ; Intracellular Signaling Peptides and Proteins ; MRAS protein, human ; SHOC2 protein, human ; raf Kinases (EC 2.7.11.1) ; PPP1CB protein, human (EC 3.1.3.16) ; Protein Phosphatase 1 (EC 3.1.3.16) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2018-10-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1720352115
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Article ; Online: SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers.

Jones, Greg G / Del Río, Isabel Boned / Sari, Sibel / Sekerim, Aysen / Young, Lucy C / Hartig, Nicole / Areso Zubiaur, Itziar / El-Bahrawy, Mona A / Hynds, Rob E / Lei, Winnie / Molina-Arcas, Miriam / Downward, Julian / Rodriguez-Viciana, Pablo

Nature communications

2019 Volume 10, Issue 1, Page(s) 2532

Abstract: Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority of human cancers, has been hindered in the clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays a key role in RAF-ERK pathway activation by ... ...

Abstract	Targeted inhibition of the ERK-MAPK pathway, upregulated in a majority of human cancers, has been hindered in the clinic by drug resistance and toxicity. The MRAS-SHOC2-PP1 (SHOC2 phosphatase) complex plays a key role in RAF-ERK pathway activation by dephosphorylating a critical inhibitory site on RAF kinases. Here we show that genetic inhibition of SHOC2 suppresses tumorigenic growth in a subset of KRAS-mutant NSCLC cell lines and prominently inhibits tumour development in autochthonous murine KRAS-driven lung cancer models. On the other hand, systemic SHOC2 ablation in adult mice is relatively well tolerated. Furthermore, we show that SHOC2 deletion selectively sensitizes KRAS- and EGFR-mutant NSCLC cells to MEK inhibitors. Mechanistically, SHOC2 deletion prevents MEKi-induced RAF dimerization, leading to more potent and durable ERK pathway suppression that promotes BIM-dependent apoptosis. These results present a rationale for the generation of SHOC2 phosphatase targeted therapies, both as a monotherapy and to widen the therapeutic index of MEK inhibitors.
MeSH term(s)	Animals ; Apoptosis ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Female ; HEK293 Cells ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; MAP Kinase Signaling System ; Male ; Mice, Knockout ; Mice, Nude ; Mutation ; Neoplasm Transplantation ; Protein Kinase Inhibitors/pharmacology ; Protein Multimerization ; raf Kinases/antagonists & inhibitors ; raf Kinases/genetics ; raf Kinases/metabolism ; ras Proteins/metabolism
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Protein Kinase Inhibitors ; SHOC2 protein, human ; raf Kinases (EC 2.7.11.1) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2019-06-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-10367-x
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Article: Ras ubiquitination: coupling spatial sorting and signal transmission.

Rodriguez-Viciana, Pablo / McCormick, Frank

Cancer cell

2006 Volume 9, Issue 4, Page(s) 243–244

Abstract: H-Ras, N-Ras, and K-Ras proteins have distinct biological properties, despite ubiquitous expression and similar affinities for regulators and effectors. C-terminal hypervariable regions that distinguish H-Ras, N-Ras, and K-Ras proteins direct them to ... ...

Abstract	H-Ras, N-Ras, and K-Ras proteins have distinct biological properties, despite ubiquitous expression and similar affinities for regulators and effectors. C-terminal hypervariable regions that distinguish H-Ras, N-Ras, and K-Ras proteins direct them to distinct membrane compartments, where they may encounter regulators and effectors at different local concentrations. Jura and coworkers now report that these membrane-targeting domains direct differential ubiquitination of Ras proteins and so provide a molecular mechanism to explain the sorting process and, perhaps, some of the dramatic differences in biological potency among H-Ras, N-Ras, and K-Ras proteins.
MeSH term(s)	Animals ; Humans ; Protein Binding ; Signal Transduction ; Ubiquitin/metabolism ; ras Proteins/genetics ; ras Proteins/metabolism
Chemical Substances	Ubiquitin ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2006-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccr.2006.03.025
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Zs.MG 104: Show issues

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Article: Polyoma and SV40 proteins differentially regulate PP2A to activate distinct cellular signaling pathways involved in growth control.

Rodriguez-Viciana, Pablo / Collins, Crista / Fried, Mike

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

2006 Volume 103, Issue 51, Page(s) 19290–19295

Abstract: Binding of Src family kinases to membrane-associated polyoma virus middle T-antigen (PyMT) can result in the phosphorylation of PyMT tyrosine 250, which serves as a docking site for the binding of Shc and subsequent activation of the Raf-MEK-ERK (MAP) ... ...

Abstract	Binding of Src family kinases to membrane-associated polyoma virus middle T-antigen (PyMT) can result in the phosphorylation of PyMT tyrosine 250, which serves as a docking site for the binding of Shc and subsequent activation of the Raf-MEK-ERK (MAP) kinase cascade. In a screen for PyMT variants that could not activate the ARF tumor suppressor, we isolated a cytoplasmic nontransforming mutant (MTA) that encoded a C-terminal truncated form of the PyMT protein. Surprisingly, MTA was able to strongly activate the MAP kinase pathway in the absence of Src family kinase and Shc binding. Interestingly, the polyoma small T-antigen (PyST), which shares with MTA both partial amino acid sequence homology and cellular location, also activates the MAP kinase cascade. Activation of the MAP kinase cascade by both MTA and PyST has been demonstrated to be PP2A-dependent. Neither MTA nor PyST activate the phosphorylation of AKT. The SV40 small T-antigen, which is similar to PyST in containing a J domain and in binding to the PP2A AC dimer, does not activate the MAP kinase cascade, but does stimulate phosphorylation of AKT in a PP2A-dependent manner. These findings highlight a novel role of PP2A in stimulating the MAP kinase cascade and indicate that the similar polyoma and SV40 small T-antigens influence PP2A to activate discrete cellular signaling pathways involved in growth control.
MeSH term(s)	Animals ; Antigens, Polyomavirus Transforming/genetics ; Antigens, Polyomavirus Transforming/metabolism ; Blotting, Western ; Cell Line ; Cell Proliferation ; Immunoprecipitation ; Mitogen-Activated Protein Kinases/metabolism ; Mutation/genetics ; Phosphoprotein Phosphatases/metabolism ; Phosphorylation ; Rats ; Signal Transduction/genetics
Chemical Substances	Antigens, Polyomavirus Transforming ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Phosphoprotein Phosphatases (EC 3.1.3.16)
Language	English
Publishing date	2006-12-19
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0609343103
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Article: Characterization of interactions between ras family GTPases and their effectors.

Rodriguez-Viciana, Pablo / McCormick, Frank

Methods in enzymology

2006 Volume 407, Page(s) 187–194

Abstract: Ras family GTPases (RFGs), when in their active GTP-bound state, interact with a wide array of downstream effectors to regulate many biological functions in different cell types. How signal specificity among the closely related family members is achieved ...

Abstract	Ras family GTPases (RFGs), when in their active GTP-bound state, interact with a wide array of downstream effectors to regulate many biological functions in different cell types. How signal specificity among the closely related family members is achieved is still poorly understood. There is both promiscuity and specificity in the ability of RFGs to interact with and regulate the various effector families, as well as isoforms within those families. RFGs seem to have individual blueprints of effector interactions, and specificity should be considered in the context of the full spectrum of effectors they regulate. The sequencing of the genome has identified a remarkably diverse number of proteins with domains homologous to the Ras-binding domain (RBD) of known Ras effectors and, thus, with the potential to interact with Ras and/or other RFGs. In addition, other proteins without known RBD types are known to behave as RFG effectors, suggesting even more complexity in the number of effector interactions. Determining which of these many candidates are "true" effectors and characterizing their specificity is a critical step to understanding the specific signaling properties and biological functions of the various RFGs.
MeSH term(s)	Animals ; GTP Phosphohydrolases/metabolism ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/metabolism ; Humans ; Transfection ; raf Kinases/metabolism ; ras Proteins/metabolism
Chemical Substances	Guanosine Diphosphate (146-91-8) ; Guanosine Triphosphate (86-01-1) ; raf Kinases (EC 2.7.11.1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; ras Proteins (EC 3.6.5.2)
Language	English
Publishing date	2006
Publishing country	United States
Document type	Journal Article
ISSN	0076-6879
ISSN	0076-6879
DOI	10.1016/S0076-6879(05)07016-3
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