Phosphatidylinositol-3-OH kinase direct target of Ras

Rodríguez‐Viciana, Pablo; Warne, Patricia H.; Dhand, Ritu; Vanhaesebroeck, Bart; Gout, Ivan; Fry, Michael; Waterfield, Michael D.; Downward, Julian

doi:10.1038/370527a0

Cited by 1,850 publications

(1,319 citation statements)

References 35 publications

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“…This observation suggested that the signalling pathway mediated by periostin was acting through the PI3K/AKT pathway rather than through the RAF/ MEK/ERK pathway. However, our results do not exclude the possibility that K-Ras could contribute to periostin signalling by directly activating the PI3K complex (Rodriguez-Viciana et al, 1994).…”

Section: Discussioncontrasting

confidence: 90%

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

Baril¹,

Gangeswaran²,

Mahon³

et al. 2006

Oncogene

257

244

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Pancreatic ductal adenocarcinoma is a devastating disease, characterized by a rapid progression and poor treatment response. Using gene expression profiling of pancreatic cancer tissues, we previously identified periostin as a potential diagnostic and therapeutic target. In this study, we report the overexpression of periostin in a larger set of pancreatic cancer tissues and show that although the periostin transcript is exclusively expressed in tumour cells, the protein product is only detected in the extracellular matrix adjacent to cancer cells. Using an enzyme-linked immunosorbent assay (ELISA) assay, we show significantly increased levels of periostin in the sera of pancreatic cancer patients compared to non-cancer controls. We demonstrate that periostin promotes the invasiveness of tumour cells by increasing the motility of cells without inducing expression of proteases, and enhances the survival of tumour cells exposed to hypoxic conditions. At the molecular level, we provide evidence that the a 6 b 4 integrin complex acts as the cell receptor of periostin in pancreatic cancer cells and that interaction promotes phosphorylation of focal adhesion kinase (FAK) and protein kinase B (AKT) though activation of the PI3 kinase pathway, but not the RAS/MEK/ERK pathway. These findings suggest an important role of periostin in pancreatic cancer and provide a rationale to study periostin for diagnostic and therapeutic applications.

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Section: Discussioncontrasting

confidence: 90%

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

Baril¹,

Gangeswaran²,

Mahon³

et al. 2006

Oncogene

257

244

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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: 76%

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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“…This pathway mediates the signal into the nuclei, leading to activation of primary-response nuclear protooncogenes such as c-fos and c-myc by phosphorylation [5,6]. However, it is possible that ras p21 has effector proteins other than Raf-1, since ras p21 possesses multiple functions, pl20-GAP, p110 subunit of PI3-kinase, and MEKK are possible effector proteins of ras p21 in that these proteins interact with the GTP-bound form of ras p21 and that these proteins have an influence downstream of ras p21 in various signaling pathway [14][15][16][17]. However, several evidence has suggested that pl20-GAP and p110 subunit of PI3-kinase act as regulators of ras p21 [18,19].…”

Section: Introductionmentioning

confidence: 99%

rap1 p21 regulates the interaction of ras p21 with RGL, a new effector protein of ras p21

et al. 1995

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We have recently found that ralGDS family members (RGL and ralGDS) are putative effector proteins of ras p21. rapl p21 is a small GTP-binding protein which has the same amino acid sequence as the effector loop of ras p21. We examined the effect of rapl p21 on the interaction of ras p21 with RGL. The GTP-bound form of rapl p21 interacted with RGL as well as did ras p21. rapl p21 inhibited the interaction of ras p21 with RGL. RGL was phosphorylated by cyclic AMP-dependent protein kinase (protein kinase A). Phosphorylation of RGL did not affect its binding to ras p21 and rapl p21 under the conditions that phosphorylation of Raf-1 reduced its affinity for ras p21. These results demonstrate that rapl p21 but not protein kinase A regulates the interaction of ras p21 with RGL and suggest that rapl p21 and protein kinase A may cooperate to distinguish the signal of ras p21 to RGL from that to Raf-1.

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Phosphatidylinositol-3-OH kinase direct target of Ras

Cited by 1,850 publications

References 35 publications

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway

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

rap1 p21 regulates the interaction of ras p21 with RGL, a new effector protein of ras p21

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