Antiapoptotic Signalling by the Insulin-Like Growth Factor I Receptor, Phosphatidylinositol 3-Kinase, and Akt

Kulik, George; Klippel, Anke; Weber, Michael J.

doi:10.1128/mcb.17.3.1595

Cited by 984 publications

(809 citation statements)

References 67 publications

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“…Similarly to the observation made for IGF-IR signalling in Rat-1 cells by Kulik et al (1997), the MAPK inhibitor PD098059 had no e ect on survival signalling of wt-TrkA against MycER TM or U.V.-induced apoptosis in our cell-system (data not shown). These data are consistent with the fact that NGF induced survival in primary sympathetic neurones is not blocked by PD098059 (Creedon et al, 1996;Virdee and Tolkovsky, 1996) suggesting that ± at least in the cell systems mentioned above ± MAPK does not add to the survival signals of IGF-IR or TrkA.…”

Section: Resultssupporting

confidence: 87%

“…Moreover, overexpression of constitutively active forms of the PI3-kinase target Akt/PKB has been shown to be su cient to block apoptosis in a number of cell types (Dudek et al, 1997;Kulik et al, 1997;Kau mannZeh et al, 1997;Khwaja et al, 1997). NGFstimulated TrkA activates PI3-kinase in both PC12 cells and in ®broblasts expressing TrkA (Carter and Downes, 1992;Ra oni and Bradshaw, 1992;Solto et al, 1992;Ohmichi et al, 1992).…”

Section: Resultsmentioning

confidence: 99%

“…Both, the MAPK and the PI3-kinase pathways seem to be required for IGF-I to inhibit apoptosis of di erentiated PC12 cells following NGF withdrawal (Parrizas et al, 1997). An anti-apoptotic role of PI3-kinase is further supported by the ®nding that the PI3-kinase-activated serine/threonine kinase Akt/PKB is required for IGF-Iinduced survival of serum-deprived neurones (Dudek et al, 1997) and by the observation that activated Akt/ PKB is su cient to block U.V.-induced apoptosis in ®broblasts (Kulik et al, 1997). Furthermore, activated forms of both PI3-kinase and Akt/PKB suppress c-Myc induced apoptosis in Rat-1MycER TM cells when overexpressed (Kau mann-Zeh et al, 1997).…”

Section: Introductionmentioning

confidence: 94%

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Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

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Survival signalling by ligand-activated tyrosine kinase receptors plays a crucial role in maintaining the balance between cell viability and apoptosis in multicellular organisms. To identify receptor domains and pathways involved in survival signalling, the nerve growth factor receptor TrkA was expressed in Rat-1/MycER TM ®broblasts. We demonstrate that wt-TrkA receptor delays c-Myc-, U.V.-and Cycloheximide-induced apoptosis and activates targets such as the mitogen-activated protein kinase (MAPK) Erk2 and the serine/threonine kinase Akt/PKB, both of which have been implicated in survival signalling. TrkA mutated within its SHC binding site (Y490F) delays c-Myc-induced apoptosis without activating endogenous Akt/PKB. In contrast, the TrkA Y490F mutant receptor does not delay U.V.-induced apoptosis whilst TrkA mutated at its PLC-g binding site (Y785F) is capable of protecting from apoptosis induced by c-Myc or U.V. treatment. The double mutant TrkA YY490/785FF fails to block either of these two apoptotic stimuli. While PI3-kinase inhibitors LY294002 and Wortmannin competely block survival signalling following U.V. treatment, neither drug a ects the ability of TrkA to block c-Myc-induced apoptosis. We show that the Akt/PKB pathway is essential for NGF stimulated TrkA survival signalling in the case of U.V.-induced apoptosis, but that apoptosis induced by c-Myc is also blocked by a novel, Akt/PKB-independent, pathway. These observations suggest that TrkA can activate di erent survival signalling pathways, which can interfere with speci®c apoptotic pathways.

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Section: Resultssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

See 1 more Smart Citation

Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

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“…9 PI3-K is thought to be one of the key molecules involved in the signaling pathways of activated receptor tyrosine kinases and in the regulation of cell growth, motility, and morphogenesis. [33][34][35] Shayesteh et al 36 demonstrated that the copy number of PIK3CA, the gene encoding the P110a catalytic subunit of PI3-K, was increased in approximately 80% of primary ovarian cancers and several ovarian cancer cell lines. It has also been demonstrated that another PI3-K inhibitor, LY294002, significantly inhibited tumor growth and ascites formation by ovarian carcinoma in vivo and markedly inhibited cancer cell proliferation in vitro, suggesting an important role of PI3-K in the growth of ovarian carcinoma.…”

Section: Actinin-4 and Ovarian Cancer S Yamamoto Et Almentioning

confidence: 99%

Actinin-4 expression in ovarian cancer: a novel prognostic indicator independent of clinical stage and histological type

Yamamoto

Tsuda

Honda³

et al. 2007

Modern Pathology

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Actinin-4 is an isoform of non-muscular a-actinin and actin-bundling protein. By enhancing cell motility, actinin-4 shows different biological properties from another isoform of non-muscular actinin 'actinin-1' and variable clinicopathological implications of actinin-4 have been demonstrated in some human malignancies such as breast cancers, lung cancers, and colorectal cancers. We herein described the clinicopathological and prognostic significance of actinin-4 expression in ovarian cancers. Actinin-4 expression was analyzed immunohistochemically in 265 primary ovarian carcinomas: 116 serous, 71 clear cell, 43 endometrioid, and 35 mucinous adenocarcinomas. With reference to endothelial immunoreactivity, cytoplasmic expression of actinin-4 was classified as either low (including negative) or high. Then, various parameters such as patients' characteristics, histopathological findings including E-cadherin and b-catenin immunoreactivity, and clinical outcome, were compared between groups showing differences in the intensity or intracellular distribution of actinin-4 immunoreactivity. High expression of actinin-4 was demonstrated in 137 (57%) cases and was associated with serous histology (P ¼ 0.0075), high histological grade (Po0.0001), an advanced disease stage (P ¼ 0.036), a high degree of residual disease after initial surgery (P ¼ 0.0047), poor patient outcome (5-year survival: 52.4% in the high-expression group vs 71.9% in the low expression group, P ¼ 0.0043 by log-rank test), and also with reduced E-cadherin and preserved b-catenin expressions (P ¼ 0.0097 and 0.017, respectively). Nuclear immunoreactivity for actinin-4 was detected in 20 (7.5%) cases and was associated with low histological grade (P ¼ 0.0079) but not with other variables. Multivariate analysis showed that high actinin-4 expression was an independent prognostic factor for overall survival, as well as a high degree of residual disease and clear-cell histology. Accumulation of actinin-4 in the cytoplasm may be related to a higher propensity for tumor invasiveness and metastasis, probably by enhancing cell motility, and could be a novel prognostic indicator for patients with ovarian carcinomas.

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“…6, S6 and S7), which is surprising because loss of PTEN is often associated with suppression of apoptosis and enhanced cell survival (Brunet et al., 1999; Kulik, Klippel, & Weber, 1997). These responses are elicited in immortalized cell lines or cell lines following irradiation‐induced DNA damage, which are not normal, WT cells or conditions.…”

Section: Discussionmentioning

confidence: 99%

Impaired caudal fin‐fold regeneration in zebrafish deficient for the tumor suppressor Pten

et al. 2017

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Zebrafish are able to completely regrow their caudal fin‐folds after amputation. Following injury, wound healing occurs, followed by the formation of a blastema, which produces cells to replace the lost tissue in the final phase of regenerative outgrowth. Here we show that, surprisingly, the phosphatase and tumor suppressor Pten, an antagonist of phosphoinositide‐3‐kinase (PI3K) signaling, is required for zebrafish caudal fin‐fold regeneration. We found that homozygous knock‐out mutant (ptena−/−ptenb−/−) zebrafish embryos, lacking functional Pten, did not regenerate their caudal fin‐folds. AKT phosphorylation was enhanced, which is consistent with the function of Pten. Reexpression of Pten, but not catalytically inactive mutant Pten‐C124S, rescued regeneration, as did pharmacological inhibition of PI3K. Blastema formation, determined by in situ hybridization for the blastema marker junbb, appeared normal upon caudal fin‐fold amputation of ptena−/−ptenb−/− zebrafish embryos. Whole‐mount immunohistochemistry using specific markers indicated that proliferation was arrested in embryos lacking functional Pten, and that apoptosis was enhanced. Together, these results suggest a critical role for Pten by limiting PI3K signaling during the regenerative outgrowth phase of zebrafish caudal fin‐fold regeneration.

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Antiapoptotic Signalling by the Insulin-Like Growth Factor I Receptor, Phosphatidylinositol 3-Kinase, and Akt

Cited by 984 publications

References 67 publications

Specific TrkA survival signals interfere with different apoptotic pathways

Specific TrkA survival signals interfere with different apoptotic pathways

Actinin-4 expression in ovarian cancer: a novel prognostic indicator independent of clinical stage and histological type

Impaired caudal fin‐fold regeneration in zebrafish deficient for the tumor suppressor Pten

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