Evidence for a Ras-dependent extracellular signal-regulated protein kinase (ERK) cascade.

Robbins, David J.; Cheng, Mangeng; Zhen, Erzhen; Vanderbilt, Colleen A.; Feig, Larry A.; Cobb, Melanie H.

doi:10.1073/pnas.89.15.6924

Cited by 199 publications

(110 citation statements)

References 33 publications

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“…Ras plays a major role in integrating the signaling between the receptors and the kinase modules since the expression of a dominant negative, competitively inhibitory mutant of Ras, (N17-Ras) inhibits Raf-MKK-ERK signaling in diverse cell types (de VriesSmitts et al, 1992; Robbins et al, 1992;Thomas et al, 1992;Wood et al, 1992). Raf-1 is the most predominant upstream kinase that is involved in the activation of MKKs (Dent et al, 1992;Howe et al, 1992;Kyriakis et al, 1992).…”

Section: Map Kinase Kinase-1 and Map Kinase Kinase-2mentioning

confidence: 99%

Signaling by dual specificity kinases

1998

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Dual speci®city kinases that phosphorylate the Thr-and Tyr-residues within the TXY motif of MAP-kinases of play a central role in the regulation of various processes of cell growth. These dual speci®city kinases also known as MAP kinase kinases are constituents of the sequential kinase signaling modules. Seven distinct mammalian MAP kinases kinases have been identi®ed. Some of the unique signaling properties of these kinases are discussed here.

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Section: Map Kinase Kinase-1 and Map Kinase Kinase-2mentioning

confidence: 99%

Signaling by dual specificity kinases

1998

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“…The MAP kinases or ERKs are downstream elements of the NGF signaling cascade that are activated by a Ras-dependent pathway (Robbins et al, 1992). To assess the capacity of the Trk mutants to regulate this pathway, we compared NGF-mediated activation of MAPK by Western blotting with an antiactive MAPK-antibody.…”

Section: Activation Of Downstream Signaling Elementsmentioning

confidence: 99%

Molecular dissection of TrkA signal transduction pathways mediating differentiation in human neuroblastoma cells

et al. 2000

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Activation of the neurotrophin receptor TrkA by its ligand nerve growth factor (NGF) initiates a cascade of signaling events leading to neuronal di erentiation in vitro and might play an important role in the di erentiation of favorable neuroblastomas (NB) in vivo. To study TrkA signal transduction pathways and their e ects on di erentiation in NB, we stably expressed wild-type TrkA and ®ve di erent TrkA mutants in the NGF unresponsive human NB cell line SH-SY5Y. Resulting clones were characterized by TrkA mRNA and protein expression, and by autophosphorylation of the receptor. Introduction of wild-type TrkA restored NGF responsiveness of SH-SY5Y cells, as demonstrated by morphological di erentiation, activation of mitogenactivated protein kinases (MAPK) and induction of immediate-early genes. Expression of TrkA in the absence of NGF resulted in growth inhibition of transfectants compared to parental cells, whereas NGFtreatment increased their proliferation rate. Analysis of downstream signal transduction pathways indicated that NGF-induced di erentiation was dependent on TrkA kinase activity. Our data suggest that several redundant pathways are present further downstream, but activation of the RAS/MAPK signaling pathway seems to be of major importance for NGF mediated di erentiation of NB cells. Our results also show that the signaling e ector SH2-B is a substrate of NGF-mediated Trk signaling in NB, whereas it is not activated by NGF in rat pheochromocytoma PC12 cells. This might explain the di erences we observed in TrkA signaling between neuroblastoma and PC12 cells. Further insight into TrkA signaling may suggest new options for the treatment of NB. Oncogene (2000) 19, 2043 ± 2051.Keywords: neuroblastoma; tyrosine kinase receptors; neurotrophins; signal transduction; di erentiation IntroductionNeuroblastoma is one of the most common pediatric neoplasms and is derived from the neural crest. Neurotrophic factors and their tyrosine kinase receptors (Trks) play an important role in the pathogenesis, biology and clinical behavior of NB (Brodeur, 1993). Observations from several independent studies suggest that high expression of the neurotrophin receptor TrkA is present in NB with favorable biological features and highly correlated with patient survival (Nakagawara et al., 1993;Kogner et al., 1993). Activation of TrkA by its ligand NGF leads to survival and di erentiation of TrkA expressing cells in vitro (Klein et al., 1991) and might play an important role in the regression or di erentiation of NB in vivo.Signal transduction pathways used by TrkA have been studied mainly in the PC12 rat pheochromocytoma cell line. Following NGF binding, TrkA receptors rapidly become phosphorylated on tyrosine residues, and their tyrosine kinase domain is activated (Klein et al., 1991). Phosphorylated tyrosine residues in the TrkA cytoplasmic domain serve as anchors for binding downstream signaling molecules (Schlessinger and Ullrich, 1992). Proteins known to become phosphorylated and activated in response to NGF include phosph...

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“…Extensive studies in the last several years have demonstrated that the members of mitogen activated protein kinase (MAPKs) family constitute a superfamily of proteins that include extracellular-signalregulated protein kinases (Erks) and c-Jun N-terminal kinases/stress-activated protein kinases (JNKs/SAPKs) and P38 kinase (Boulton et al, 1990(Boulton et al, , 1991Davis, 1994;Kyriakis et al, 1994;Robbins et al, 1992). These kinases belong to the activated serine/threonine kinases, which are uniquely identi®ed by the ThrXaa-Tyr dual-phosphorylation motif, where Xaa is Glu, Pro and Gly for Erks, JNKs/SAPKs and P38 kinase, respectively (Cobb et al, 1994;Kallunki et al, 1994;Sluss et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

The extracellular-signal-regulated protein kinases (Erks) are required for UV-induced AP-1 activation in JB6 cells

Huang

Dong

1999

Oncogene

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Mitogen activated protein (MAP) kinase belongs to a large family of serine/threonine protein kinases, including extracellular-signal-regulated protein kinases (Erks), P38 kinase and c-Jun N-terminal kinases (JNKs). Although previous work has shown that both Erks and JNKs are activated in cells in response to ultraviolet (UV) irradiation, most studies have focused only on the role of JNKs in UV-induced AP-1 activation. Hence, the role of Erks in UV-induced AP-1 activity is not well de®ned. We here have investigated this issue by using MAP kinase kinase (MEK 1 IntroductionExtensive studies in the last several years have demonstrated that the members of mitogen activated protein kinase (MAPKs) family constitute a superfamily of proteins that include extracellular-signalregulated protein kinases (Erks) and c-Jun N-terminal kinases/stress-activated protein kinases (JNKs/SAPKs) and P38 kinase (Boulton et al., 1990(Boulton et al., , 1991Davis, 1994;Kyriakis et al., 1994;Robbins et al., 1992). These kinases belong to the activated serine/threonine kinases, which are uniquely identi®ed by the ThrXaa-Tyr dual-phosphorylation motif, where Xaa is Glu, Pro and Gly for Erks, JNKs/SAPKs and P38 kinase, respectively (Cobb et al., 1994;Kallunki et al., 1994;Sluss et al., 1994). Phosphorylation of both tyrosine and threonine residues, which are found in the activation segment of the kinase domain, is essential for full kinase activity (Coso et al., 1995;Dalton and Treisman, 1992). The activation of MAPKs may be by translocation to the nucleus, where these kinases phosphorylate target transcription factors such as AP-1 (Coso et al., 1995;Huang et al., 1996a;Rosenberger and Bowden, 1996). It is believed that Erks are strongly activated and play a critical role in transmitting signals initiated by 12-0-tetradecanoylphorbol-13-acetate (TPA) and growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF) (Cowley et al., 1994;Dalton and Treisman, 1992;L'Allemain et al., 1992;PageÁ s et al., 1993;Robbins et al., 1993;Wan et al., 1996;Xia et al., 1995). Whereas the JNKs/SAPKs and P38 kinases are potently activated by various forms of stress, such as ultraviolet light (UV), heat shock and in¯ammation (Adler et al., 1995(Adler et al., , 1996BuÈ scher et al., 1988; Denhardt, 1996;Ludwig et al., 1996;Minden et al., 1994; SaÂ nchez et al., 1994), the activation of these pathways is not mutually exclusive. For example, heat shock and UV irradiation partially activate the Erk1/Erk2 cascade and EGF partially activates the JNKs/SAPKs pathway (Denhardt, 1996, Minden et al., 1994. Thus, understanding how such speci®city is maintained and the extent and signi®cance of crosstalk between each signaling cascade are very important subjects requiring further investigation.Erks (Erk1 and Erk2) were the ®rst members of the MAPKs superfamily whose cDNA were cloned (Boulton et al., 1990(Boulton et al., , 1991Cobb et al., 1994). The Ras?Raf?MEK?Erks cascade is the signaling cascade that leads to Erks activation. Previous st...

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Evidence for a Ras-dependent extracellular signal-regulated protein kinase (ERK) cascade.

Cited by 199 publications

References 33 publications

Signaling by dual specificity kinases

Signaling by dual specificity kinases

Molecular dissection of TrkA signal transduction pathways mediating differentiation in human neuroblastoma cells

The extracellular-signal-regulated protein kinases (Erks) are required for UV-induced AP-1 activation in JB6 cells

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