Akt activation by growth factors is a multiple-step process: the role of the PH domain

Bellacosa, Alfonso; Chan, Tung O.; Ahmed, Naheed N; Datta, Ketaki; Malstrom, Scott; Stokoe, David; McCormick, Frank; Feng, Jinan; Tsichlis, Philip N.

doi:10.1038/sj.onc.1201947

Cited by 489 publications

(442 citation statements)

References 41 publications

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“…One of the most extensively studied targets of PDK-1 was AKT, which can be activated by phosphorylation on two residues (T308 and S473) for full oncogenic activity (Bellacosa et al, 1998). Although phosphorylation of AKT at T308 was mediated by PDK-1 (Alessi et al, 1997;Wick et al, 2000a), phosphorylation of AKT at S473 may be involved by other kinases including putative PDK-2 (Hresko et al, 2003), integrin-linked kinase (ILK) (Persad et al, 2001), protein kinase C-a (Partovian and Simons, 2004), DNAdependent protein kinase C (Feng et al, 2004) or Rictor-mTOR complex (Sarbassov et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…The oncogenic effects of AKT in human cancers depended on its ability of inducing multiple downstream cascades to promote cell survival, tumour growth and progression (Bellacosa et al, 1998;Franke et al, 2003;Osaki et al, 2004). Deregulation of this pathway leads to upregulation of AKT signalling cascades was commonly found in variety of human cancers including breast carcinoma (Vivanco and Sawyers, 2002;Lee et al, 2005;Levine et al, 2005).…”

Section: Phosphorylation Of Akt In Breast Carcinomamentioning

confidence: 99%

“…Its activation has been implicated in a number of human cancers by promoting proliferation and inhibiting apoptosis caused by various death stimuli (Del Peso et al, 1997;Franke et al, 1997;Kulik et al, 1997). AKT is activated in response to survival signals from growth factors or cytokines via mechanisms involving PI3-K and PDK-1 (Alessi et al, 1997;Franke et al, 1997;Kulik et al, 1997;Bellacosa et al, 1998). Upregulation of AKT by mutation of PTEN (a tumour suppressor gene that antagonises AKT pathway) or amplification PIK3CA (encodes catalytic subunit of PI3-K) were reported in a number of human cancers including breast carcinoma (Vivanco and Sawyers, 2002;Lee et al, 2005;Levine et al, 2005).…”

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confidence: 99%

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Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

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Activation of kinases signalling pathways contributes to various malignant phenotypes in human cancers, including breast tumour. To examine the possible activation of these signalling molecules, we examined the phosphorylation status in 12 protein kinases and transcription factors in normal primary human mammary epithelial cells, telomerase-immortalised human breast epithelial cell line, and two breast cancer lines, MDA-MB-468 and MCF-7, using Kinexus phosphorylated protein screening assays. The phosphorylation of FAK, mTOR, p70S6K, and PDK-1 were elevated in both breast cancer cell lines, whereas the phosphorylation of AKT, EGFR, ErbB2/ Her2, PDGFR, Shc, and Stat3 were elevated in only one breast cancer line compared to normal primary mammary epithelial cells and telomerase-immortalised breast epithelial cells. The same findings were confirmed by Western blotting and by kinase assays. We further substantiated the phosphorylation status of these molecules in tissue microarray slides containing 89 invasive breast cancer tissues as well as six normal mammary tissues with immunohistochemistry staining using phospho-specific antibodies. Consistent findings were obtained as greater than 70% of invasive breast carcinomas expressed moderate to high levels of phosphorylated PDK-1, AKT, p70S6K, and EGFR. In sharp contrast, phosphorylation of the same proteins was nearly undetectable or was at low levels in normal mammary tissues under the same assay. Elevated phosphorylation of PDK-1, AKT, mTOR, p70S6K, S6, EGFR, and Stat3 were highly associated with invasive breast tumours (Po0.05). Taken together, our results suggest that activation of these kinase pathways by phosphorylation may in part account for molecular pathogenesis of human breast carcinoma. Particularly, moderate to high level of PDK-1 phosphorylation was found in 86% of high-grade metastasised breast tumours. This is the first report demonstrating phosphorylation of PDK-1 is frequently elevated in breast cancer with concomitantly increased phosphorylation of downstream kinases, including AKT, mTOR, p70S6K, S6, and Stat3. This finding thus suggested PDK-1 may promote oncogenesis in part through the activation of AKT and p70S6K and rationalised that PDK-1 as well as downstream components of PDK-1 signalling pathway may be promising therapeutic targets to treat breast cancer. Breast cancer remains to be a major cause of death in women worldwide, despite improvements in cancer prevention, early detection, treatment, and understanding the molecular pathogenesis. It hence demands an urgent need to unveil the exact mechanism of oncogenesis and tumour progression, which may prelude the development of new strategies for treatment. Breast carcinoma emerges through multistep processes progressing from hyperplasia to premalignant change, in situ carcinoma, invasion, and distal metastasis, in concomitant with gain of oncogenic activities and loss of tumour suppressor gene functions.Protein kinases have been implicated in playing crucial roles in regulating cell growth, met...

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Section: Discussionmentioning

confidence: 99%

Section: Phosphorylation Of Akt In Breast Carcinomamentioning

confidence: 99%

mentioning

confidence: 99%

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Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

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“…The E40K mutation in the pleckstrin homology domain enhances the affinity for PIP 3 while retaining growth factor inducibility. 28 DKI cells were retrovirally transduced with pMSCV-IRES-GFP vectors encoding WT-Akt, E40K-Akt or a kinase-dead (K179M) Akt, and GFP-positive mass populations isolated by cell sorting. We compared the activation of targets downstream of PI3-kinase/ Akt in p110*-and E40K-expressing cells.…”

Section: Csf-1-dependent Mitogenesis Requires Both Erk and Pi3-kinasementioning

confidence: 99%

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Lee

States

2006

Cell Death Differ

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Colony-stimulating factor-1 (CSF-1) is essential for macrophage growth, differentiation and survival. Myeloid cells expressing a CSF-1 receptor mutant (DKI) show markedly impaired CSF-1-mediated proliferation and survival, accompanied by absent signal transducers and activators of transcription 3 (Stat3) phosphorylation and reduced PI3-kinase/Akt activity. Restoring phosphatidylinositol 3-kinase (PI3-kinase) but not Stat3 signals reverses the mitogenic defect. CSF-1-induced proliferation and survival are sensitive to glycolytic inhibitors, 2-deoxyglucose and 3-bromopyruvate. Consistent with a critical role for PI3-kinase-regulated glycolysis, DKI cells reconstituted with active PI3-kinase or Akt are hypersensitive to these inhibitors. CSF-1 upregulates hexokinase II (HKII) expression through PI3-kinase, and PI3-kinase transcriptionally activates the HKII promoter. Moreover, HKII overexpression partially restores mitogenicity. In contrast, Bcl-x L expression does not enhance long-term proliferation, although short-term cell death is suppressed in a glycolysis-independent manner. This study identifies robust PI3-kinase activation as essential for optimal CSF-1-mediated mitogenesis in myeloid cells, in part through regulation of HKII and support of glycolysis.

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“…PIP 3 then recruits AKT to the membrane where it is sequentially phosphorylated on T 308 and S 473 [27,28]. Once activated, AKT modulates downstream effectors relevant to the regulation of cell growth (i.e.…”

Section: Introductionmentioning

confidence: 99%

Mutation of Y179 on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3K-and Akt-dependent manner

Fulvio

Frondorf

Gómez‐Cambronero

2008

Cellular Signalling

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Phospholipase D2 (PLD2), one of the two mammalian members of the PLD family, has been implicated in cell proliferation, transformation, tumor progression and survival. However, as precise mechanistic details are still unknown, we investigated here if the PLD2 isoform would signal through the PI3K/AKT pathway. Transient expression of PLD2 in COS7 cells with either the WT or with a Y179F mutant, resulted in an increased basal phosphorylation of AKT in residues T 308 and S 473 , in a PI3K-dependent manner. Transfection of PLD2-Y179F (but not the wild type) caused an increased (>2-fold) DNA synthesis even in the absence of extracellular stimuli. Other signaling mechanisms downstream such PLD/PI3K dependence (that might lead to DNA synthesis regulation), were further studied. PLD2-Y179F caused an increase in phosphorylation of p42/p44 ERK and in the expression of G 0 /G 1 phase transition markers, p21 CIP and PCNA, and these effects, too, were dependent on PI3K. Interestingly, Akt once activated, enabled the phosphorylation of PLD2 on residue T 175 , an effect that was inhibited by LY296004. Lastly, if PLD2-Y179F is further mutated in residue K758 (PLD2 Y179F-K758R), which renders inactive a catalytic site, DNA synthesis is then abrogated, indicating that the activity of the enzyme (i.e. synthesis of PA) is necessary for the observed effects.In conclusion, the unavailability of residue Y179 on PLD2 to become phosphorylated leads to an augmentation of DNA synthesis concomitantly with MEK and AKT phosphorylation, in a process that is dependent on PI3K and independent of any extracellular stimuli. This might be critical for the maintenance of the PLD2-regulated proliferative status.

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Akt activation by growth factors is a multiple-step process: the role of the PH domain

Cited by 489 publications

References 41 publications

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

Colony-stimulating factor-1 requires PI3-kinase-mediated metabolism for proliferation and survival in myeloid cells

Mutation of Y179 on phospholipase D2 (PLD2) upregulates DNA synthesis in a PI3K-and Akt-dependent manner

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