Ras-Dependent Induction of Cellular Responses by Constitutively Active Phosphatidylinositol-3 Kinase

Hu, Qianjin; Klippel, Anke; Muslin, Anthony J.; Fantl, Wendy J.; Williams, Lewis T.

doi:10.1126/science.7701328

Cited by 529 publications

(441 citation statements)

References 19 publications

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“…In our experiments, MT binding to Shc and PI3K also seems to be essential for complete MAPK activation (data not shown). This is consistent with cooperation between the Ras and the PI3K pathways for full MAPK activation (Rodriguez-Viciana et al, 1994;Hu et al, 1995;Marra et al, 1995). However, high AP-1 activity is observed in the 250phe mutant (that does not bind Shc) even though the Erk1 activity displayed by this cell line is low.…”

Section: Discussionsupporting

confidence: 75%

Mapping of polyomavirus middle T domain that is responsible for AP-1 activation

et al. 1998

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Cell transformation by Polyomavirus middle T (MT) oncoprotein involves binding and activation of several cytoplasmic proteins that participate in growth factorsinduced mitogenic signal transduction to the nucleus. We have previously reported that the AP-1 transcriptional complex is a target for MT during cell transformation. To analyse the interactions between MT and cellular proteins that are required for constitutive AP-1 activation, we compared wild type and transformation-defective MT mutant cell lines. High AP-1 activity, assessed by gel mobility shift assays, displayed by MT-overexpressing cells, is dependent on MT binding to phosphatidylinositol-3 kinase (P13K). Treatment with wortmannin (a speci®c P13K inhibitor) leads to decreased AP-1 activity. Supershift and Western blot analysis with speci®c antisera, indicate that JunB and cJun, but not cFos or FosB are present in the AP-1 complex. The results con®rm the AP-1 complex as a downstream MT target and indicate that AP-1 activation may not be su cient for cell transformation, since two transformation-defective MT mutants (250phe and MT322) display high AP-1 activity.

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Section: Discussionsupporting

confidence: 75%

Mapping of polyomavirus middle T domain that is responsible for AP-1 activation

et al. 1998

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“…It has been shown that PI 3-kinase through its protein kinase activity, regulates Ras, Raf, or ERK kinase (MEK) (Hu et al, 1995;Pandey et al, 1999;Bondeva et al, 1998). PI 3-kinase can directly activate MEK through protein phosphorylation Bondeva et al, 1998), or PDK-1 can directly bind and activate MEK (Sato et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Lower Phosphoinositide 3-Kinase (PI 3-kinase) Activity and Differential Expression Levels of Selective Catalytic and Regulatory PI 3-Kinase Subunit Isoforms in Prefrontal Cortex and Hippocampus of Suicide Subjects

Dwivedi

Rizavi

Teppen

et al. 2007

Neuropsychopharmacol

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Phosphoinositide 3 (PI 3)-kinase is one of the key signaling enzymes that participates in a myriad of physiological functions in brain and is utilized by neurotrophins to mediate neuronal plasticity, cell survival, and inhibition of apoptosis for several neuronal subtypes. Our recent demonstration that expression of neurotrophic factors and activation of the receptor tyrosine kinase B are significantly altered in postmortem brain of suicide subjects led us to examine whether suicide brain is associated with alterations in PI 3-kinase signaling. In prefrontal cortex (PFC), hippocampus, and cerebellum of suicide (n ¼ 28) and nonpsychiatric control (n ¼ 21) subjects we examined catalytic activation of PI 3-kinase, and mRNA and protein levels of regulatory (p85a, p85b) and catalytic (p110a, p110b) subunits of PI 3-kinase. It was observed that the catalytic activity of PI 3-kinase was significantly reduced in PFC and hippocampus of suicide subjects compared with nonpsychiatric control subjects. Competitive PCR analysis revealed significantly reduced mRNA expression of p85b and p110a and increased expression of p85a subunit isoforms in PFC and hippocampus of suicide subjects. Alterations in these catalytic and regulatory subunits were accompanied by changes in their respective protein levels. These changes were not present in cerebellum of suicide subjects. Also, these changes were present in all suicide subjects irrespective of psychiatric diagnosis. Our findings of reduced activation and altered expression of specific PI 3-kinase regulatory and catalytic subunit isoforms demonstrate abnormalities in this signaling pathway in postmortem brain of suicide subjects and suggest possible involvement of aberrant PI 3-kinase signaling in the pathogenic mechanisms of suicide.

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“…In fact both wortmannin or p85 dominant negative e ciently block Gas6 survival activities, together with its mitogenic e ects (Goruppi et al, 1997) and Ras was indeed shown to be exclusively required for Gas6-dependent mitogenesis (this manuscript). Accordingly Hu et al (1995) reported that, at least in some systems, Ras might behave as a downstream PI3K e ector. Interestingly an overall reduction of cell survival was observed when RasN17, but not the Ras blocking antibody, was microinjected.…”

Section: Discussionmentioning

confidence: 99%