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Article ; Online: Protein kinase C: poised to signal.

Newton, Alexandra C

American journal of physiology. Endocrinology and metabolism

2009 Volume 298, Issue 3, Page(s) E395–402

Abstract: Nestled at the tip of a branch of the kinome, protein kinase C (PKC) family members are poised ... the level of signaling-competent PKC in the cell. Disruption of this regulation results ... to transduce signals emanating from the cell surface. Cell membranes provide the platform for PKC function, supporting ...

Abstract	Nestled at the tip of a branch of the kinome, protein kinase C (PKC) family members are poised to transduce signals emanating from the cell surface. Cell membranes provide the platform for PKC function, supporting the maturation of PKC through phosphorylation, its allosteric activation by binding specific lipids, and, ultimately, promoting the downregulation of the enzyme. These regulatory mechanisms precisely control the level of signaling-competent PKC in the cell. Disruption of this regulation results in pathophysiological states, most notably cancer, where PKC levels are often grossly altered. This review introduces the PKC family and then focuses on recent advances in understanding the cellular regulation of its diacylglycerol-regulated members.
MeSH term(s)	Computer Simulation ; Models, Biological ; Protein Kinase C/metabolism ; Signal Transduction/physiology
Chemical Substances	Protein Kinase C (EC 2.7.11.13)
Language	English
Publishing date	2009-11-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	603841-4
ISSN	1522-1555 ; 0193-1849
ISSN (online)	1522-1555
ISSN	0193-1849
DOI	10.1152/ajpendo.00477.2009
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Article ; Online: Unveiling Phytoconstituents with Inhibitory Potential Against Tyrosine-Protein Kinase Fyn: A Comprehensive Virtual Screening Approach Targeting Alzheimer's Disease.

Alrouji, Mohammed / Majrashi, Taghreed A / Alhumaydhi, Fahad A / Zari, Ali / Zari, Talal A / Al Abdulmonem, Waleed / Sharaf, Sharaf E / Shahwan, Moyad / Anwar, Saleha / Shamsi, Anas / Atiya, Akhtar

Journal of Alzheimer's disease : JAD

2023 Volume 96, Issue 2, Page(s) 827–844

Abstract: Background: Tyrosine-protein kinase Fyn (Fyn) is a critical signaling molecule involved in various ... among bioactive phytoconstituents against tyrosine-protein kinase Fyn.: Methods: Through a comprehensive ... exhibitedcompatibility and stability, indicating the formation of robust protein-ligand complexes. A significant array ...

Abstract	Background: Tyrosine-protein kinase Fyn (Fyn) is a critical signaling molecule involved in various cellular processes, including neuronal development, synaptic plasticity, and disease pathogenesis. Dysregulation of Fyn kinase has been implicated in various complex diseases, including neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, as well as different cancer types. Therefore, identifying small molecule inhibitors that can inhibit Fyn activity holds substantial significance in drug discovery. Objective: The aim of this study was to identify potential small-molecule inhibitors among bioactive phytoconstituents against tyrosine-protein kinase Fyn. Methods: Through a comprehensive approach involving molecular docking, drug likeliness filters, and molecular dynamics (MD) simulations, we performed a virtual screening of a natural compounds library. This methodology aimed to pinpoint compounds potentially interacting with Fyn kinase and inhibiting its activity. Results: This study finds two potential natural compounds: Dehydromillettone and Tanshinone B. These compoundsdemonstrated substantial affinity and specific interactions towards the Fyn binding pocket. Their conformations exhibitedcompatibility and stability, indicating the formation of robust protein-ligand complexes. A significant array of non-covalentinteractions supported the structural integrity of these complexes. Conclusion: Dehydromillettone and Tanshinone B emerge as promising candidates, poised for further optimization as Fynkinase inhibitors with therapeutic applications. In a broader context, this study demonstrates the potential of computationaldrug discovery, underscoring its utility in identifying compounds with clinical significance. The identified inhibitors holdpromise in addressing a spectrum of cancer and neurodegenerative disorders. However, their efficacy and safety necessitatevalidation through subsequent experimental studies.
MeSH term(s)	Humans ; Alzheimer Disease ; Molecular Docking Simulation ; Neoplasms ; Tyrosine ; Proto-Oncogene Proteins c-fyn/antagonists & inhibitors ; Phytochemicals/pharmacology
Chemical Substances	tanshinone (03UUH3J385) ; Tyrosine (42HK56048U) ; FYN protein, human (EC 2.7.10.2) ; Proto-Oncogene Proteins c-fyn (EC 2.7.10.2) ; Phytochemicals
Language	English
Publishing date	2023-10-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-230828
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Article ; Online: Multi-state recognition pathway of the intrinsically disordered protein kinase inhibitor by protein kinase A.

Olivieri, Cristina / Wang, Yingjie / Li, Geoffrey C / V S, Manu / Kim, Jonggul / Stultz, Benjamin R / Neibergall, Matthew / Porcelli, Fernando / Muretta, Joseph M / Thomas, David Dt / Gao, Jiali / Blumenthal, Donald K / Taylor, Susan S / Veglia, Gianluigi

eLife

2020 Volume 9

Abstract: ... protein kinase A (PKA-C) is orchestrated by an intrinsically disordered protein kinase inhibitor, PKI ... protein domains) are able to operate multiple functions such as inhibiting the kinase while recruiting ... featured by PKA-C/PKI complex represents a paradigm on how disordered, ancillary proteins (or ...

Abstract	In the nucleus, the spatiotemporal regulation of the catalytic subunit of cAMP-dependent protein kinase A (PKA-C) is orchestrated by an intrinsically disordered protein kinase inhibitor, PKI, which recruits the CRM1/RanGTP nuclear exporting complex. How the PKA-C/PKI complex assembles and recognizes CRM1/RanGTP is not well understood. Using NMR, SAXS, fluorescence, metadynamics, and Markov model analysis, we determined the multi-state recognition pathway for PKI. After a fast binding step in which PKA-C selects PKI's most competent conformations, PKI folds upon binding through a slow conformational rearrangement within the enzyme's binding pocket. The high-affinity and pseudo-substrate regions of PKI become more structured and the transient interactions with the kinase augment the helical content of the nuclear export sequence, which is then poised to recruit the CRM1/RanGTP complex for nuclear translocation. The multistate binding mechanism featured by PKA-C/PKI complex represents a paradigm on how disordered, ancillary proteins (or protein domains) are able to operate multiple functions such as inhibiting the kinase while recruiting other regulatory proteins for nuclear export.
MeSH term(s)	Active Transport, Cell Nucleus ; Animals ; Cyclic AMP-Dependent Protein Kinases/genetics ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cytoplasm ; Escherichia coli ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Karyopherins/genetics ; Karyopherins/metabolism ; Magnetic Resonance Spectroscopy ; Markov Chains ; Mice ; Protein Kinase Inhibitors/metabolism ; Rabbits ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/metabolism ; Exportin 1 Protein
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Karyopherins ; Protein Kinase Inhibitors ; Receptors, Cytoplasmic and Nuclear ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11)
Language	English
Publishing date	2020-04-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.55607
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Article ; Online: Bipartite Role of Heat Shock Protein 90 (Hsp90) Keeps CRAF Kinase Poised for Activation.

Mitra, Shahana / Ghosh, Baijayanti / Gayen, Nilanjan / Roy, Joydeep / Mandal, Atin K

The Journal of biological chemistry

2016 Volume 291, Issue 47, Page(s) 24579–24593

Abstract: CRAF kinase maintains cell viability, growth, and proliferation by participating in the MAPK ... identified the bipartite role of Hsp90 in chaperoning CRAF kinase. Hsp90 facilitates Ser-621 phosphorylation ... of CRAF and prevents the kinase from degradation. Co-chaperone Cdc37 assists in this phosphorylation event ...

Abstract	CRAF kinase maintains cell viability, growth, and proliferation by participating in the MAPK pathway. Unlike BRAF, CRAF requires continuous chaperoning by Hsp90 to retain MAPK signaling. However, the reason behind the continuous association of Hsp90 with CRAF is still elusive. In this study, we have identified the bipartite role of Hsp90 in chaperoning CRAF kinase. Hsp90 facilitates Ser-621 phosphorylation of CRAF and prevents the kinase from degradation. Co-chaperone Cdc37 assists in this phosphorylation event. However, after folding, the stability of the kinase becomes insensitive to Hsp90 inhibition, although the physical association between Hsp90 and CRAF remains intact. We observed that overexpression of Hsp90 stimulates MAPK signaling by activating CRAF. The interaction between Hsp90 and CRAF is substantially increased under an elevated level of cellular Hsp90 and in the presence of either active Ras (Ras
MeSH term(s)	Amino Acid Substitution ; Enzyme Activation/physiology ; HEK293 Cells ; HSP90 Heat-Shock Proteins/genetics ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; MAP Kinase Signaling System/physiology ; Mutation, Missense ; Oncogene Protein p21(ras)/genetics ; Oncogene Protein p21(ras)/metabolism ; Phosphorylation/physiology ; Proto-Oncogene Proteins c-raf/genetics ; Proto-Oncogene Proteins c-raf/metabolism
Chemical Substances	HSP90 Heat-Shock Proteins ; Proto-Oncogene Proteins c-raf (EC 2.7.11.1) ; Oncogene Protein p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2016-10-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.746420
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Article ; Online: Potential role for phosphatidylinositol transfer protein (PITP) family in lipid transfer during phospholipase C signalling.

Cockcroft, Shamshad / Garner, Kathryn

Advances in biological regulation

2013 Volume 53, Issue 3, Page(s) 280–291

Abstract: ... for both phospholipase C and phosphoinositide-3-kinases as well as required as an intact lipid to regulate ion channels ... PITPs are therefore ideally poised to couple phosphatidylinositol delivery to the PI kinases ... could couple PA and PI transport bidirectionally during phospholipase C signalling. ...

Abstract	The hallmark of mammalian phosphatidylinositol transfer proteins (PITPs) is to transfer phosphatidylinositol between membrane compartments. In the mammalian genome, there are three genes that code for soluble PITP proteins, PITPα, PITPβ and RdgBβ and two genes that code for membrane-associated multi-domain proteins (RdgBαI and II) containing a PITP domain. PITPα and PITPβ constitute Class I PITPs whilst the RdgB proteins constitute Class II proteins based on sequence analysis. The PITP domain of both Class I and II can sequester one molecule of phosphatidylinositol (PI) in its hydrophobic cavity. Therefore, in principle, PITPs are therefore ideally poised to couple phosphatidylinositol delivery to the PI kinases for substrate provision for phospholipases C during cell activation. Since phosphatidylinositol (4,5)bisphosphate plays critical roles in cells, particularly at the plasma membrane, where it is a substrate for both phospholipase C and phosphoinositide-3-kinases as well as required as an intact lipid to regulate ion channels and the actin cytoskeleton, homeostatic mechanisms to maintain phosphatidylinositol(4,5)bisphosphate levels are vital. To maintain phosphatidylinositol levels, phospholipase C activation inevitably leads to the resynthesis of PI at the endoplasmic reticulum where the enzymes are located. Phosphatidic acid generated at the plasma membrane during phospholipase C activation needs to move to the ER for conversion to PI and here we provide evidence that Class II PITPs are also able to bind and transport phosphatidic acid. Thus RdgB proteins could couple PA and PI transport bidirectionally during phospholipase C signalling.
MeSH term(s)	Animals ; Humans ; Lipid Metabolism ; Multigene Family ; Phospholipid Transfer Proteins/genetics ; Phospholipid Transfer Proteins/metabolism ; Signal Transduction ; Type C Phospholipases/genetics ; Type C Phospholipases/metabolism
Chemical Substances	Phospholipid Transfer Proteins ; Type C Phospholipases (EC 3.1.4.-)
Language	English
Publishing date	2013-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2667413-0
ISSN	2212-4934 ; 2212-4926
ISSN (online)	2212-4934
ISSN	2212-4926
DOI	10.1016/j.jbior.2013.07.007
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Article ; Online: Incomplete folding upon binding mediates Cdk4/cyclin D complex activation by tyrosine phosphorylation of inhibitor p27 protein.

Ou, Li / Ferreira, Antonio M / Otieno, Steve / Xiao, Limin / Bashford, Donald / Kriwacki, Richard W

The Journal of biological chemistry

2011 Volume 286, Issue 34, Page(s) 30142–30151

Abstract: p27(Kip1) (p27), an intrinsically disordered protein, regulates the various Cdk/cyclin complexes ... that control cell cycle progression. The kinase inhibitory domain of p27 contains a cyclin-binding subdomain (D1), a Cdk ... tyrosine kinase Abl. Importantly, tyrosine phosphorylation (of p27) relieves Cdk inhibition by p27, enabling ...

Abstract	p27(Kip1) (p27), an intrinsically disordered protein, regulates the various Cdk/cyclin complexes that control cell cycle progression. The kinase inhibitory domain of p27 contains a cyclin-binding subdomain (D1), a Cdk-binding subdomain (D2), and a linker helix subdomain that connects D1 and D2. Here, we report that, despite extensive sequence conservation between Cdk4/cyclin D1 (hereafter Cdk4/cyclin D) and Cdk2/cyclin A, the thermodynamic details describing how the individual p27 subdomains contribute to equally high affinity binding to these two Cdk/cyclin complexes are strikingly different. Differences in enthalpy/entropy compensation revealed that the D2 subdomain of p27 folds incompletely when binding Cdk4/cyclin D versus Cdk2/cyclin A. Incomplete binding-induced folding exposes tyrosine 88 of p27 for phosphorylation by the nonreceptor tyrosine kinase Abl. Importantly, tyrosine phosphorylation (of p27) relieves Cdk inhibition by p27, enabling cell cycle entry. Furthermore, the interaction between a conserved hydrophobic patch on cyclin D and subdomain D1 is much weaker than that with cyclin A; consequently, a construct containing subdomains D1 and LH (p27-D1LH) does not inhibit substrate binding to Cdk4/cyclin D as it does to Cdk2/cyclin A. Our results provide a mechanism by which Cdk4 (within the p27/Cdk4/cyclin D complex) is poised to be activated by extrinsic mitogenic signals that impinge upon p27 at the earliest stage of cell division. More broadly, our results further illustrate the regulatory versatility of intrinsically disordered proteins.
MeSH term(s)	Cyclin D/chemistry ; Cyclin D/genetics ; Cyclin D/metabolism ; Cyclin-Dependent Kinase 4/chemistry ; Cyclin-Dependent Kinase 4/genetics ; Cyclin-Dependent Kinase 4/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/chemistry ; Cyclin-Dependent Kinase Inhibitor p27/genetics ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Entropy ; Humans ; Hydrophobic and Hydrophilic Interactions ; Multiprotein Complexes/chemistry ; Multiprotein Complexes/genetics ; Multiprotein Complexes/metabolism ; Phosphorylation/physiology ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-abl/chemistry ; Proto-Oncogene Proteins c-abl/genetics ; Proto-Oncogene Proteins c-abl/metabolism
Chemical Substances	CDKN1B protein, human ; Cyclin D ; Multiprotein Complexes ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; Proto-Oncogene Proteins c-abl (EC 2.7.10.2) ; CDK4 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22)
Language	English
Publishing date	2011-06-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M111.244095
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Article ; Online: Human kinome profiling identifies a requirement for AMP-activated protein kinase during human cytomegalovirus infection.

Terry, Laura J / Vastag, Livia / Rabinowitz, Joshua D / Shenk, Thomas

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

2012 Volume 109, Issue 8, Page(s) 3071–3076

Abstract: ... to HCMV replication. Multiple elements of the AMP-activated protein kinase (AMPK) pathway scored ... and from the altered activity of multiple kinases. Here we report a comprehensive RNAi screen ... which predicts that 106 cellular kinases influence growth of the virus, most of which were not previously linked ...

Abstract	Human cytomegalovirus (HCMV) modulates numerous cellular signaling pathways. Alterations in signaling are evident from the broad changes in cellular phosphorylation that occur during HCMV infection and from the altered activity of multiple kinases. Here we report a comprehensive RNAi screen, which predicts that 106 cellular kinases influence growth of the virus, most of which were not previously linked to HCMV replication. Multiple elements of the AMP-activated protein kinase (AMPK) pathway scored in the screen. As a regulator of carbon and nucleotide metabolism, AMPK is poised to activate many of the metabolic pathways induced by HCMV infection. An AMPK inhibitor, compound C, blocked a substantial portion of HCMV-induced metabolic changes, inhibited the accumulation of all HCMV proteins tested, and markedly reduced the production of infectious progeny. We propose that HCMV requires AMPK or related activity for viral replication and reprogramming of cellular metabolism.
MeSH term(s)	AMP-Activated Protein Kinases/metabolism ; Cell Line ; Cytomegalovirus/drug effects ; Cytomegalovirus/physiology ; Cytomegalovirus Infections/enzymology ; Cytomegalovirus Infections/virology ; Humans ; Metabolome/drug effects ; Protein Kinase Inhibitors/pharmacology ; Proteomics/methods ; Signal Transduction/drug effects ; Virus Replication/drug effects
Chemical Substances	Protein Kinase Inhibitors ; AMP-Activated Protein Kinases (EC 2.7.11.31)
Language	English
Publishing date	2012-02-06
Publishing country	United States
Document type	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.1200494109
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Article: Locostatin Disrupts Association of Raf Kinase Inhibitor Protein With Binding Proteins by Modifying a Conserved Histidine Residue in the Ligand-Binding Pocket.

Beshir, Anwar B / Argueta, Christian E / Menikarachchi, Lochana C / Gascón, José A / Fenteany, Gabriel

Forum on immunopathological diseases and therapeutics

2011 Volume 2, Issue 1, Page(s) 47–58

Abstract: Raf kinase inhibitor protein (RKIP) interacts with a number of different proteins and regulates ... not only disrupts interactions of RKIP with Raf-1 kinase, but also with G protein-coupled receptor ... kinase 2. In contrast, we found that locostatin does not disrupt binding of RKIP to two other proteins ...

Abstract	Raf kinase inhibitor protein (RKIP) interacts with a number of different proteins and regulates multiple signaling pathways. Here, we show that locostatin, a small molecule that covalently binds RKIP, not only disrupts interactions of RKIP with Raf-1 kinase, but also with G protein-coupled receptor kinase 2. In contrast, we found that locostatin does not disrupt binding of RKIP to two other proteins: inhibitor of κB kinase α and transforming growth factor β-activated kinase 1. These results thus imply that different proteins interact with different regions of RKIP. Locostatin's mechanism of action involves modification of a nucleophilic residue on RKIP. We observed that after binding RKIP, part of locostatin is slowly hydrolyzed, leaving a smaller RKIP-butyrate adduct. We identified the residue alkylated by locostatin as His86, a highly conserved residue in RKIP's ligand-binding pocket. Computational modeling of the binding of locostatin to RKIP suggested that the recognition interaction between small molecule and protein ensures that locostatin's electrophilic site is poised to react with His86. Furthermore, binding of locostatin would sterically hinder binding of other ligands in the pocket. These data provide a basis for understanding how locostatin disrupts particular interactions of RKIP with RKIP-binding proteins and demonstrate its utility as a probe of specific RKIP interactions and functions.
Language	English
Publishing date	2011-05-13
Publishing country	United States
Document type	Journal Article
ISSN	2151-8017
ISSN	2151-8017
DOI	10.1615/forumimmundisther.v2.i1.60
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Article: Mutational activation of ErbB2 reveals a new protein kinase autoinhibition mechanism.

Fan, Ying-Xin / Wong, Lily / Ding, Jinhui / Spiridonov, Nikolay A / Johnson, Richard C / Johnson, Gibbes R

The Journal of biological chemistry

2007 Volume 283, Issue 3, Page(s) 1588–1596

Abstract: Autoinhibition plays a key role in the control of protein kinase activity. ErbB2 is a unique ... receptor-tyrosine kinase that does not bind ligand but possesses an extracellular domain poised to engage ... of mitogen-activated protein kinase. Molecular modeling suggests that the ErbB2 kinase domain is stabilized in an inactive state via ...

Abstract	Autoinhibition plays a key role in the control of protein kinase activity. ErbB2 is a unique receptor-tyrosine kinase that does not bind ligand but possesses an extracellular domain poised to engage other ErbBs. Little is known about the molecular mechanism for ErbB2 catalytic regulation. Here we show that ErbB2 kinase is strongly autoinhibited, and a loop connecting the alphaC helix and beta4 sheet within the kinase domain plays a major role in the control of kinase activity. Mutations of two Gly residues at positions 776 and 778 in this loop dramatically increase ErbB2 catalytic activity. Kinetic analysis demonstrates that mutational activation is due to approximately 10- and approximately 7-fold increases in ATP binding affinity and turnover number, respectively. Expression of the activated ErbB2 mutants in cells resulted in elevated ligand-independent ErbB2 autophosphorylation, ErbB3 phosphorylation, and stimulation of mitogen-activated protein kinase. Molecular modeling suggests that the ErbB2 kinase domain is stabilized in an inactive state via a hydrophobic interaction between the alphaC-beta4 and activation loops. Importantly, many ErbB2 human cancer mutations have been identified in the alphaC-beta4 loop, including the activating G776S mutation studied here. Our findings reveal a new kinase regulatory mechanism in which the alphaC-beta4 loop functions as an intramolecular switch that controls ErbB2 activity and suggests that loss of alphaC-beta4 loop-mediated autoinhibition is involved in oncogenic activation of ErbB2.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; COS Cells ; Catalysis ; Chlorocebus aethiops ; Enzyme Activation ; ErbB Receptors/metabolism ; HSP90 Heat-Shock Proteins/metabolism ; Humans ; Kinetics ; Models, Molecular ; Mutation/genetics ; Peptides/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Receptor, ErbB-2/antagonists & inhibitors ; Receptor, ErbB-2/chemistry ; Receptor, ErbB-2/metabolism ; Signal Transduction ; Substrate Specificity
Chemical Substances	HSP90 Heat-Shock Proteins ; Peptides ; Adenosine Triphosphate (8L70Q75FXE) ; ErbB Receptors (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2007-11-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M708116200
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Article ; Online: Neuronal and intestinal protein kinase d isoforms mediate Na+ (salt taste)-induced learning.

Fu, Ya / Ren, Min / Feng, Hui / Chen, Lu / Altun, Zeynep F / Rubin, Charles S

Science signaling

2009 Volume 2, Issue 83, Page(s) ra42

Abstract: Ubiquitously expressed protein kinase D (PKD) isoforms are poised to disseminate signals carried ... Cbeta4 homolog) and TPA-1 (a protein kinase Cdelta homolog) are upstream regulators of DKF-2 isoforms ... that PKDs couple DAG signals to regulation of sodium ion (Na+)-induced learning. EGL-8 (a phospholipase ...

Abstract	Ubiquitously expressed protein kinase D (PKD) isoforms are poised to disseminate signals carried by diacylglycerol (DAG). However, the in vivo regulation and functions of PKDs are poorly understood. We show that the Caenorhabditis elegans gene, dkf-2, encodes not just DKF-2A, but also a second previously unknown isoform, DKF-2B. Whereas DKF-2A is present mainly in intestine, we show that DKF-2B is found in neurons. Characterization of dkf-2 null mutants and transgenic animals expressing DKF-2B, DKF-2A, or both isoforms revealed that PKDs couple DAG signals to regulation of sodium ion (Na+)-induced learning. EGL-8 (a phospholipase Cbeta4 homolog) and TPA-1 (a protein kinase Cdelta homolog) are upstream regulators of DKF-2 isoforms in vivo. Thus, pathways containing EGL-8-TPA-1-DKF-2 enable learning and behavioral plasticity by receiving, transmitting, and cooperatively integrating environmental signals targeted to both neurons and intestine.
MeSH term(s)	Animals ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans Proteins/metabolism ; Caenorhabditis elegans Proteins/physiology ; Intestines/enzymology ; Learning/drug effects ; Learning/physiology ; Lipase/metabolism ; Lipase/physiology ; Neurons/enzymology ; Protein Isoforms ; Protein Kinase C/metabolism ; Protein Kinase C/physiology ; Protein-Tyrosine Kinases/metabolism ; Protein-Tyrosine Kinases/physiology ; Saccharomyces cerevisiae Proteins ; Sodium, Dietary/pharmacology ; Taste/physiology
Chemical Substances	Caenorhabditis elegans Proteins ; Protein Isoforms ; Saccharomyces cerevisiae Proteins ; Sodium, Dietary ; TPA-1 protein, C elegans (EC 2.7.1.-) ; DKF-2 protein, C elegans (EC 2.7.10.-) ; protein kinase D (EC 2.7.10.-) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Protein Kinase C (EC 2.7.11.13) ; Lipase (EC 3.1.1.3)
Language	English
Publishing date	2009-08-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.2000224
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