Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor

Traverse, Sarah; Gómez, Néstor; Paterson, Hugh; Marshall, Christopher J.; Cohen, Philip

doi:10.1042/bj2880351

Cited by 871 publications

(689 citation statements)

References 20 publications

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“…These ®ndings suggest that di erences exist between the rapid stimulatory signal induced by EGF and the prolonged signalling mediated by constitutively active Cbl, Src, Ras and Raf. EGF stimulation is known to induce a rapid activation of MAP kinases which reaches a peak within 2 ± 5 min and returns to a basal level by 1 h (Buday and Downward, 1993b) whereas sustained activation is associated with translocation of MAP kinases to the nucleus (Traverse et al, 1992(Traverse et al, , 1994Nguyen et al, 1993;Dikic et al, 1994). In this study however we did not detect an increase in nuclear ERKs in 70Z-Cbl transformed cells (data not shown).…”

Section: Characterization Of Downstream E Ects Of 70z-cbl and V-cblcontrasting

confidence: 41%

Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl

Thien

Langdon

1997

Oncogene

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The 120 kD product of the c-Cbl oncogene is a prominent substrate of protein tyrosine kinases that lacks a known catalytic activity but possesses an array of binding sites for cytoplasmic signalling proteins. An oncogenic form of Cbl was recently identi®ed in the 70Z/ 3 pre-B cell lymphoma which has a small deletion at the N-terminus of the Ring ®nger domain. This form of Cbl, termed 70Z-Cbl, exhibits an enhanced level of tyrosine phosphorylation compared with c-Cbl. Here we demonstrate that the expression of 70Z-Cbl induces a tenfold enhancement in the kinase activity of the EGF receptor in serum-starved and EGF-stimulated cells. In serumstarved cells this results in EGF receptor autophosphorylation and the recruitment of Grb2, Shc and Sos1 but does not induce a corresponding increase in MAP kinase activity. Furthermore the expression of 70Z-Cbl greatly enhances EGF-induced tyrosine phosphorylation of the protein tyrosine phosphatase SHP-2. We also show that the Cbl/EGF receptor complex is predominantly associated with CrkII and is distinct to the Grb2/ Shc/Sos1 complex that associates with the EGF receptor. These ®ndings therefore demonstrate a biochemical e ect of an oncogenic Cbl protein and support predictions from C. elegans that Cbl functions as regulator of receptor tyrosine kinases.

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Section: Characterization Of Downstream E Ects Of 70z-cbl and V-cblcontrasting

confidence: 41%

Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl

Thien

Langdon

1997

Oncogene

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“…Based on earlier published data we tested this possibility and found that dominant negative Rac1 completely blocked nuclear translocation of ERK1 by middle-T. This observation is not necessarily in contradiction to other reports showing that the activity of ERKs is independent of Rac1 (Minden et al, 1995;Coso et al, 1995; since phosphorylation of ERK by MEK is not su cient for nuclear translocation (Traverse et al, 1992).…”

Section: Discussionmentioning

confidence: 63%

A role for the small GTPase Rac in polyomavirus middle-T antigen-mediated activation of the serum response element and in cell transformation

et al. 1997

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The oncogenic proteins encoded by papovaviruses, the tumor antigens, have been extensively used as model systems to study mitogenic signaling and cell transformation. These proteins stimulate cell growth in cultured cells and induce tumors in virus infected or transgenic animals. One of these proteins, polyomavirus middle-T, acts like a constitutively activated tyrosine growth factor receptor. Middle-T recruits several cellular enzymes into a multifunctional complex located at cellular membranes. This results in the activation of cellular enzymes involved in the regulation of cell signaling, like tyrosine kinases of the Src family, a phosphatidylinositol 3-kinase and a GDP/GTP exchange factor for Ras. These activities are all required for stimulation of cell growth by middle-T and activate members of the MAP kinase family. Here we investigate the role of T antigen-activated pathways in the stimulation of transcription of immediate early genes. These genes are essential for progression of resting cells into S phase. Our data show that Rho family GTPases play an essential role in cell transformation by middle-T. Furthermore, we demonstrate that the c-fos promoter is activated by two Ras-initiated signaling cascades. One is Raf-dependent and requires binding of SHC and PI 3-kinase to the middle-T complex. This pathway signals via ternary complex factor (TCF) to the serum response element (SRE) of the c-fos promoter. Signaling to TCF by Raf also depends on functional Rac, but not CDC42, as demonstrated in luciferase reporter assays with an ETS domain-containing promoter. The second pathway is Raf-independent, does not require SHC but functional PI 3-kinase, and transduces signals via Rac to serum response factor (SRF). Microinjection of dominant negative Rac1 blocks nuclear translocation of ERK1 in middle-T-expressing cells. This lends support to the idea that the two signaling cascades initiated by Ras show crosstalk at the level of MAP kinase-mediated signaling to nuclear transcription factors.

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“…In addition to a few differentially regulated genes with unknown function for the course of CDDP-induced apoptosis, we noted a sustained high level of MEK1/2 mRNA expression in NCCIT cells before and after drug treatment. MEK1 and MEK2 are protein kinases that when activated (phosphorylated) are believed to dually phosphorylate only ERK1 and ERK2, thereby increasing the enzymatic activity of ERKs approximately 1000-fold over the activity found with the basal or monophosphorylated forms (Traverse et al, 1992;Lenormand et al, 1993, Robbins et al, 1993. The consequence is a phosphorylation of diverse protein kinases, transcription factors, and even cytoskeletal proteins leading to paradoxical cellular responses ranging from proliferation to apoptosis (Peyssonnaux and Eychene, 2001;Djeu et al, 2002;Lee and McCubrey, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, CDDP treatment resulted in high and sustained activation of MEK, particularly MEK1, and ERK, especially ERK2, which was strongly correlated to the apoptosis of tumour cells. Thus, it is tempting to speculate that a prolonged period of excessive phosphorylation of ERK may be necessary for its biological effect on TGCT as demonstrated for other cells types (Traverse et al, 1992;Lenormand et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

et al. 2004

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Testicular germ cell tumours (TGCT) represent the most common malignancies in young males. Whereas in 1970s, the survival rate in patients with metastatic testicular tumours was only 5%, these days, 80% of the patients treated by modern chemotherapy will survive their disease. The drug that revolutionised the cure rate for patients with metastatic testicular tumours was cisdiamminedichloroplatinum (cisplatin, CDDP). In vitro experiments on neoplastic germ cell lines showed that their exquisite sensitivity to CDDP could be attributed to p53-dependent and -independent pathways. Applying cDNA macroarray, semiquantitative RT -PCR and Western blot analyses, blocking experiments, caspase activity assays, and morphological methods, we sought here to define the p53-independent pathway(s) involved in the CDDP-induced apoptosis. For this purpose, we used the human TGCT cell line NCCIT, the mutated p53 of which is known to remain inactive during the course of CDDP-induced apoptosis. Our experiments showed that within hours of CDDP application, two prototype members of the 'mitogen-activated protein kinase' (MAPK) family, designated 'MAPK ERK kinase' (MEK) and 'extracellular signal-regulated kinase' (ERK), were dually phosphorylated and caspase-3 became active. Functional assays using MEK inhibitors demonstrated that the phosphorylation of MEK and ERK was required for the activation of caspase-3 as the executing caspase. Interestingly, experiments with the human malignant germ cell line NTERA, which is known to possess wild-type p53, revealed the same results. Thus, our data suggest that CDDP mediates its p53-independent apoptosis-inducing effect on the malignant human testicular germ cells -at least partially -through activation of the MEK -ERK signalling pathway.

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Sustained activation of the mitogen-activated protein (MAP) kinase cascade may be required for differentiation of PC12 cells. Comparison of the effects of nerve growth factor and epidermal growth factor

Cited by 871 publications

References 20 publications

Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl

Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl

A role for the small GTPase Rac in polyomavirus middle-T antigen-mediated activation of the serum response element and in cell transformation

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

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