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David T. Denhardt - One of the best experts on this subject based on the ideXlab platform.
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Signal-transducing protein Phosphorylation Cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling
Biochemical Journal, 1996Co-Authors: David T. DenhardtAbstract:The features of three distinct protein Phosphorylation Cascades in mammalian cells are becoming clear. These signalling pathways link receptor-mediated events at the cell surface or intracellular perturbations such as DNA damage to changes in cytoskeletal structure, vesicle transport and altered transcription factor activity. The best known pathway, the Ras-->Raf-->MEK-->ERK cascade [where ERK is extracellular-signal-regulated kinase and MEK is mitogen-activated protein (MAP) kinase/ERK kinase], is typically stimulated strongly by mitogens and growth factors. The other two pathways, stimulated primarily by assorted cytokines, hormones and various forms of stress, predominantly utilize p21 proteins of the Rho family (Rho, Rac and CDC42), although Ras can also participate. Diagnostic of each pathway is the MAP kinase component, which is phosphorylated by a unique dual-specificity kinase on both tyrosine and threonine in one of three motifs (Thr-Glu-Tyr, Thr-Phe-Tyr or Thr-Gly-Tyr), depending upon the pathway. In addition to activating one or more protein Phosphorylation Cascades, the initiating stimulus may also mobilize a variety of other signalling molecules (e.g. protein kinase C isoforms, phospholipid kinases, G-protein alpha and beta gamma subunits, phospholipases, intracellular Ca2+). These various signals impact to a greater or lesser extent on multiple downstream effectors. Important concepts are that signal transmission often entails the targeted relocation of specific proteins in the cell, and the reversible formation of protein complexes by means of regulated protein Phosphorylation. The signalling circuits may be completed by the Phosphorylation of upstream effectors by downstream kinases, resulting in a modulation of the signal. Signalling is terminated and the components returned to the ground state largely by dePhosphorylation. There is an indeterminant amount of cross-talk among the pathways, and many of the proteins in the pathways belong to families of closely related proteins. The potential for more than one signal to be conveyed down a pathway simultaneously (multiplex signalling) is discussed. The net effect of a given stimulus on the cell is the result of a complex intracellular integration of the intensity and duration of activation of the individual pathways. The specific outcome depends on the particular signalling molecules expressed by the target cells and on the dynamic balance among the pathways.
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signal transducing protein Phosphorylation Cascades mediated by ras rho proteins in the mammalian cell the potential for multiplex signalling
Biochemical Journal, 1996Co-Authors: David T. DenhardtAbstract:The features of three distinct protein Phosphorylation Cascades in mammalian cells are becoming clear. These signalling pathways link receptor-mediated events at the cell surface or intracellular perturbations such as DNA damage to changes in cytoskeletal structure, vesicle transport and altered transcription factor activity. The best known pathway, the Ras-->Raf-->MEK-->ERK cascade [where ERK is extracellular-signal-regulated kinase and MEK is mitogen-activated protein (MAP) kinase/ERK kinase], is typically stimulated strongly by mitogens and growth factors. The other two pathways, stimulated primarily by assorted cytokines, hormones and various forms of stress, predominantly utilize p21 proteins of the Rho family (Rho, Rac and CDC42), although Ras can also participate. Diagnostic of each pathway is the MAP kinase component, which is phosphorylated by a unique dual-specificity kinase on both tyrosine and threonine in one of three motifs (Thr-Glu-Tyr, Thr-Phe-Tyr or Thr-Gly-Tyr), depending upon the pathway. In addition to activating one or more protein Phosphorylation Cascades, the initiating stimulus may also mobilize a variety of other signalling molecules (e.g. protein kinase C isoforms, phospholipid kinases, G-protein alpha and beta gamma subunits, phospholipases, intracellular Ca2+). These various signals impact to a greater or lesser extent on multiple downstream effectors. Important concepts are that signal transmission often entails the targeted relocation of specific proteins in the cell, and the reversible formation of protein complexes by means of regulated protein Phosphorylation. The signalling circuits may be completed by the Phosphorylation of upstream effectors by downstream kinases, resulting in a modulation of the signal. Signalling is terminated and the components returned to the ground state largely by dePhosphorylation. There is an indeterminant amount of cross-talk among the pathways, and many of the proteins in the pathways belong to families of closely related proteins. The potential for more than one signal to be conveyed down a pathway simultaneously (multiplex signalling) is discussed. The net effect of a given stimulus on the cell is the result of a complex intracellular integration of the intensity and duration of activation of the individual pathways. The specific outcome depends on the particular signalling molecules expressed by the target cells and on the dynamic balance among the pathways.
Melanie H Cobb - One of the best experts on this subject based on the ideXlab platform.
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Reconstitution of mitogen-activated protein kinase Phosphorylation Cascades in bacteria. Efficient synthesis of active protein kinases
The Journal of biological chemistry, 1997Co-Authors: Andrei Khokhlatchev, Jessie M. English, Erik Schaefer, Melanie H CobbAbstract:Next Section Abstract Mitogen-activated protein (MAP) kinase pathways include a three-kinase cascade terminating in a MAP kinase family member. The middle kinase in the cascade is a MAP/extracellular signal-regulated kinase (ERK) kinase or MEK family member and is highly specific for its MAP kinase target. The first kinase in the cascade, a MEK kinase (MEKK), is characterized by its ability to activate one or more MEK family members. A two-plasmid bacterial expression system was employed to express active forms of the following MEK and MAP kinase family members: ERK1, ERK2, α-SAPK, and p38 and their upstream activators, MEK1, −2, −3, and −4. In each kinase module, the upstream activator, a constitutively active mutant of MEK1 or MEKK1, was expressed from a low copy plasmid, while one or two downstream effector kinases were expressed from a high copy plasmid with different antibiotic resistance genes and origins of replication. Consistent with their high activity, ERK1 and ERK2 were doubly phosphorylated on Tyr and Thr, were recognized by an antibody specific to the doubly phosphorylated forms, and were inactivated by either phosphoprotein phosphatase 2A or phosphotyrosine phosphatase type 1. Likewise, activated p38 and α-stress-activated protein kinase could also be inactivated by either phosphatase, and α-stress-activated protein kinase was recognized by an antibody specific to the doubly phosphorylated forms. These three purified, active MAP kinases have specific activities in the range of 0.6-2.3 μmol/min/mg. Coexpression of protein kinases with their substrates in bacteria is of great value in the preparation of numerous phosphoproteins, heretofore not possible in procaryotic expression systems.
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Reconstitution of mitogen-activated protein kinase Phosphorylation Cascades in bacteria. Efficient synthesis of active protein kinases
The Journal of biological chemistry, 1997Co-Authors: Andrei Khokhlatchev, Jessie M. English, Erik Schaefer, Melanie H CobbAbstract:Mitogen-activated protein (MAP) kinase pathways include a three-kinase cascade terminating in a MAP kinase family member. The middle kinase in the cascade is a MAP/extracellular signal-regulated kinase (ERK) kinase or MEK family member and is highly specific for its MAP kinase target. The first kinase in the cascade, a MEK kinase (MEKK), is characterized by its ability to activate one or more MEK family members. A two-plasmid bacterial expression system was employed to express active forms of the following MEK and MAP kinase family members: ERK1, ERK2, alpha-SAPK, and p38 and their upstream activators, MEK1, -2, -3, and -4. In each kinase module, the upstream activator, a constitutively active mutant of MEK1 or MEKK1, was expressed from a low copy plasmid, while one or two downstream effector kinases were expressed from a high copy plasmid with different antibiotic resistance genes and origins of replication. Consistent with their high activity, ERK1 and ERK2 were doubly phosphorylated on Tyr and Thr, were recognized by an antibody specific to the doubly phosphorylated forms, and were inactivated by either phosphoprotein phosphatase 2A or phosphotyrosine phosphatase type 1. Likewise, activated p38 and alpha-stress-activated protein kinase could also be inactivated by either phosphatase, and alpha-stress-activated protein kinase was recognized by an antibody specific to the doubly phosphorylated forms. These three purified, active MAP kinases have specific activities in the range of 0.6-2.3 micromol/min/mg. Coexpression of protein kinases with their substrates in bacteria is of great value in the preparation of numerous phosphoproteins, heretofore not possible in procaryotic expression systems.
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erks a family of protein serine threonine kinases that are activated and tyrosine phosphorylated in response to insulin and ngf
Cell, 1991Co-Authors: Teri G Boulton, Elizabeth Radzlejewska, Sharon D Morgenbesser, Ronald A Depinho, Nikos Panayotatos, Melanie H Cobb, Nancy Y Ip, David J. Robbins, George D YancopoulosAbstract:Abstract We recently described the purification and cloning of extracellular signal-regulated kinase 1 (ERK1), which appears to play a pivotal role in converting tyrosine Phosphorylation into the serine/threonine Phosphorylations that regulate downstream events. We now describe cloning and characterization of two ERK1-related kinases, ERK2 and ERK3, and provide evidence suggesting that there are additional ERK family members. At least two of the ERKs are activated in response to growth factors; their activations correlate with tyrosine phophorylation, but also depend on additional modifications. Transcripts corresponding to the three cloned ERKs are distinctly regulated both in vivo and in a differentiating cell line. Thus, this family of kinases may serve as intermediates that depend on tyrosine Phosphorylation to activate serine/threonine Phosphorylation Cascades. Individual family members may mediate responses in different developmental stages, in different cell types, or following exposure to different extracellular signals.
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ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF
Cell, 1991Co-Authors: Teri G Boulton, Elizabeth Radzlejewska, Sharon D Morgenbesser, Ronald A Depinho, Nikos Panayotatos, Melanie H Cobb, Nancy Y Ip, David J. Robbins, George D YancopoulosAbstract:Abstract We recently described the purification and cloning of extracellular signal-regulated kinase 1 (ERK1), which appears to play a pivotal role in converting tyrosine Phosphorylation into the serine/threonine Phosphorylations that regulate downstream events. We now describe cloning and characterization of two ERK1-related kinases, ERK2 and ERK3, and provide evidence suggesting that there are additional ERK family members. At least two of the ERKs are activated in response to growth factors; their activations correlate with tyrosine phophorylation, but also depend on additional modifications. Transcripts corresponding to the three cloned ERKs are distinctly regulated both in vivo and in a differentiating cell line. Thus, this family of kinases may serve as intermediates that depend on tyrosine Phosphorylation to activate serine/threonine Phosphorylation Cascades. Individual family members may mediate responses in different developmental stages, in different cell types, or following exposure to different extracellular signals.
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ERKs, extracellular signal-regulated MAP-2 kinases.
Current opinion in cell biology, 1991Co-Authors: Melanie H Cobb, David J. Robbins, Teri G BoultonAbstract:A family of protein kinases, known alternatively as microtubule-associated protein-2/myelin basic protein kinases or extracellular signal-regulated kinases, is activated by numerous hormones, growth factors and other extracellular stimuli. At least two members of this family function as intermediate kinases in protein Phosphorylation Cascades. Their mechanisms of activation may involve autoPhosphorylation, which occurs on both threonine and tyrosine residues.
Teri G Boulton - One of the best experts on this subject based on the ideXlab platform.
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erks a family of protein serine threonine kinases that are activated and tyrosine phosphorylated in response to insulin and ngf
Cell, 1991Co-Authors: Teri G Boulton, Elizabeth Radzlejewska, Sharon D Morgenbesser, Ronald A Depinho, Nikos Panayotatos, Melanie H Cobb, Nancy Y Ip, David J. Robbins, George D YancopoulosAbstract:Abstract We recently described the purification and cloning of extracellular signal-regulated kinase 1 (ERK1), which appears to play a pivotal role in converting tyrosine Phosphorylation into the serine/threonine Phosphorylations that regulate downstream events. We now describe cloning and characterization of two ERK1-related kinases, ERK2 and ERK3, and provide evidence suggesting that there are additional ERK family members. At least two of the ERKs are activated in response to growth factors; their activations correlate with tyrosine phophorylation, but also depend on additional modifications. Transcripts corresponding to the three cloned ERKs are distinctly regulated both in vivo and in a differentiating cell line. Thus, this family of kinases may serve as intermediates that depend on tyrosine Phosphorylation to activate serine/threonine Phosphorylation Cascades. Individual family members may mediate responses in different developmental stages, in different cell types, or following exposure to different extracellular signals.
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ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF
Cell, 1991Co-Authors: Teri G Boulton, Elizabeth Radzlejewska, Sharon D Morgenbesser, Ronald A Depinho, Nikos Panayotatos, Melanie H Cobb, Nancy Y Ip, David J. Robbins, George D YancopoulosAbstract:Abstract We recently described the purification and cloning of extracellular signal-regulated kinase 1 (ERK1), which appears to play a pivotal role in converting tyrosine Phosphorylation into the serine/threonine Phosphorylations that regulate downstream events. We now describe cloning and characterization of two ERK1-related kinases, ERK2 and ERK3, and provide evidence suggesting that there are additional ERK family members. At least two of the ERKs are activated in response to growth factors; their activations correlate with tyrosine phophorylation, but also depend on additional modifications. Transcripts corresponding to the three cloned ERKs are distinctly regulated both in vivo and in a differentiating cell line. Thus, this family of kinases may serve as intermediates that depend on tyrosine Phosphorylation to activate serine/threonine Phosphorylation Cascades. Individual family members may mediate responses in different developmental stages, in different cell types, or following exposure to different extracellular signals.
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ERKs, extracellular signal-regulated MAP-2 kinases.
Current opinion in cell biology, 1991Co-Authors: Melanie H Cobb, David J. Robbins, Teri G BoultonAbstract:A family of protein kinases, known alternatively as microtubule-associated protein-2/myelin basic protein kinases or extracellular signal-regulated kinases, is activated by numerous hormones, growth factors and other extracellular stimuli. At least two members of this family function as intermediate kinases in protein Phosphorylation Cascades. Their mechanisms of activation may involve autoPhosphorylation, which occurs on both threonine and tyrosine residues.
George D Yancopoulos - One of the best experts on this subject based on the ideXlab platform.
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erks a family of protein serine threonine kinases that are activated and tyrosine phosphorylated in response to insulin and ngf
Cell, 1991Co-Authors: Teri G Boulton, Elizabeth Radzlejewska, Sharon D Morgenbesser, Ronald A Depinho, Nikos Panayotatos, Melanie H Cobb, Nancy Y Ip, David J. Robbins, George D YancopoulosAbstract:Abstract We recently described the purification and cloning of extracellular signal-regulated kinase 1 (ERK1), which appears to play a pivotal role in converting tyrosine Phosphorylation into the serine/threonine Phosphorylations that regulate downstream events. We now describe cloning and characterization of two ERK1-related kinases, ERK2 and ERK3, and provide evidence suggesting that there are additional ERK family members. At least two of the ERKs are activated in response to growth factors; their activations correlate with tyrosine phophorylation, but also depend on additional modifications. Transcripts corresponding to the three cloned ERKs are distinctly regulated both in vivo and in a differentiating cell line. Thus, this family of kinases may serve as intermediates that depend on tyrosine Phosphorylation to activate serine/threonine Phosphorylation Cascades. Individual family members may mediate responses in different developmental stages, in different cell types, or following exposure to different extracellular signals.
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ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF
Cell, 1991Co-Authors: Teri G Boulton, Elizabeth Radzlejewska, Sharon D Morgenbesser, Ronald A Depinho, Nikos Panayotatos, Melanie H Cobb, Nancy Y Ip, David J. Robbins, George D YancopoulosAbstract:Abstract We recently described the purification and cloning of extracellular signal-regulated kinase 1 (ERK1), which appears to play a pivotal role in converting tyrosine Phosphorylation into the serine/threonine Phosphorylations that regulate downstream events. We now describe cloning and characterization of two ERK1-related kinases, ERK2 and ERK3, and provide evidence suggesting that there are additional ERK family members. At least two of the ERKs are activated in response to growth factors; their activations correlate with tyrosine phophorylation, but also depend on additional modifications. Transcripts corresponding to the three cloned ERKs are distinctly regulated both in vivo and in a differentiating cell line. Thus, this family of kinases may serve as intermediates that depend on tyrosine Phosphorylation to activate serine/threonine Phosphorylation Cascades. Individual family members may mediate responses in different developmental stages, in different cell types, or following exposure to different extracellular signals.
David J. Robbins - One of the best experts on this subject based on the ideXlab platform.
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erks a family of protein serine threonine kinases that are activated and tyrosine phosphorylated in response to insulin and ngf
Cell, 1991Co-Authors: Teri G Boulton, Elizabeth Radzlejewska, Sharon D Morgenbesser, Ronald A Depinho, Nikos Panayotatos, Melanie H Cobb, Nancy Y Ip, David J. Robbins, George D YancopoulosAbstract:Abstract We recently described the purification and cloning of extracellular signal-regulated kinase 1 (ERK1), which appears to play a pivotal role in converting tyrosine Phosphorylation into the serine/threonine Phosphorylations that regulate downstream events. We now describe cloning and characterization of two ERK1-related kinases, ERK2 and ERK3, and provide evidence suggesting that there are additional ERK family members. At least two of the ERKs are activated in response to growth factors; their activations correlate with tyrosine phophorylation, but also depend on additional modifications. Transcripts corresponding to the three cloned ERKs are distinctly regulated both in vivo and in a differentiating cell line. Thus, this family of kinases may serve as intermediates that depend on tyrosine Phosphorylation to activate serine/threonine Phosphorylation Cascades. Individual family members may mediate responses in different developmental stages, in different cell types, or following exposure to different extracellular signals.
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ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF
Cell, 1991Co-Authors: Teri G Boulton, Elizabeth Radzlejewska, Sharon D Morgenbesser, Ronald A Depinho, Nikos Panayotatos, Melanie H Cobb, Nancy Y Ip, David J. Robbins, George D YancopoulosAbstract:Abstract We recently described the purification and cloning of extracellular signal-regulated kinase 1 (ERK1), which appears to play a pivotal role in converting tyrosine Phosphorylation into the serine/threonine Phosphorylations that regulate downstream events. We now describe cloning and characterization of two ERK1-related kinases, ERK2 and ERK3, and provide evidence suggesting that there are additional ERK family members. At least two of the ERKs are activated in response to growth factors; their activations correlate with tyrosine phophorylation, but also depend on additional modifications. Transcripts corresponding to the three cloned ERKs are distinctly regulated both in vivo and in a differentiating cell line. Thus, this family of kinases may serve as intermediates that depend on tyrosine Phosphorylation to activate serine/threonine Phosphorylation Cascades. Individual family members may mediate responses in different developmental stages, in different cell types, or following exposure to different extracellular signals.
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ERKs, extracellular signal-regulated MAP-2 kinases.
Current opinion in cell biology, 1991Co-Authors: Melanie H Cobb, David J. Robbins, Teri G BoultonAbstract:A family of protein kinases, known alternatively as microtubule-associated protein-2/myelin basic protein kinases or extracellular signal-regulated kinases, is activated by numerous hormones, growth factors and other extracellular stimuli. At least two members of this family function as intermediate kinases in protein Phosphorylation Cascades. Their mechanisms of activation may involve autoPhosphorylation, which occurs on both threonine and tyrosine residues.