Naturally occurring ether-linked phosphatidylcholine activates phosphatidylinositol 3-kinase and stimulates cell growth

1994 ◽  
Vol 55 (1) ◽  
pp. 146-153 ◽  
Author(s):  
Siniti Misra ◽  
Amitabha Ghosh ◽  
Lyuba Varticovski
Keyword(s):  
Cell Growth ◽  
Phosphatidylinositol 3 Kinase ◽  
Naturally Occurring ◽  
Phosphatidylinositol 3

scholarly journals Cancer Cell-Derived Clusterin Modulates the Phosphatidylinositol 3′-Kinase-Akt Pathway through Attenuation of Insulin-Like Growth Factor 1 during Serum Deprivation

2008 ◽  
Vol 28 (13) ◽  
pp. 4285-4299 ◽  
Author(s):  
Hakryul Jo ◽  
Yonghui Jia ◽  
Kulandayan K. Subramanian ◽  
Hidenori Hattori ◽  
Hongbo R. Luo
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Cancer Cell ◽  
Regulatory System ◽  
Serum Deprivation ◽  
Akt Pathway ◽  
Growth Factor Signaling ◽  
Insulin Like Growth Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

ABSTRACT Cancer cells in their respective microenvironments must endure various growth-constraining stresses. Under these conditions, the cancer cell-derived factors are thought to modulate the signaling pathways between cell growth and dormancy. Here, we describe a cancer cell-derived regulatory system that modulates the phosphatidylinositol 3′-kinase (PI3K)-Akt pathway under serum deprivation stress. Through the use of biochemical purification, we reveal that cancer cell-secreted insulin-like growth factor 1 (IGF-1) and clusterin, an extracellular stress protein, constitute this regulatory system. We show that secreted clusterin associates with IGF-1 and inhibits its binding to the IGF-1 receptor and hence negatively regulates the PI3K-Akt pathway during serum deprivation. This inhibitory function of clusterin appears to prefer IGF-1, as it fails to exert any effects on epidermal growth factor signaling. We demonstrate furthermore that the constitutive activation of oncogenic signaling downstream of IGF-1 confers insensitivity to the inhibitory effects of clusterin. Thus, the interplay between cancer cell-derived clusterin and IGF-1 may dictate the outcome of cell growth and dormancy during tumorigenic progression.

Mitogenic inhibition by phorbol esters is associated with decreased phosphatidylinositol-3 kinase activation

1996 ◽  
Vol 270 (2) ◽  
pp. C619-C627 ◽  
Author(s):  
R. H. Weiss ◽  
A. P. Yabes
Keyword(s):  
Growth Factor ◽  
Cell Growth ◽  
Fibroblast Growth Factor ◽  
Phorbol Esters ◽  
Growth Factor Receptor ◽  
Dependent Manner ◽  
Fibroblast Growth ◽  
Phosphatidylinositol 3 Kinase ◽  
Signal Transfer ◽  
Phosphatidylinositol 3

In contrast to their role as potent tumor promoters, phorbol esters can cause inhibition of cell growth. Because the effect of phorbol esters occurs through activation of protein kinase C (PKC) and because activated PKC is translocated to the membrane placing it in a position to act on the intracellular portion of the growth factor receptor, we asked whether this inhibitory effect is mediated through the action of phorbol 12-myristate 13-acetate (PMA) on receptor association with the signal transfer proteins. When added to rat vascular smooth muscle (VSM) cells concurrently with basic fibroblast growth factor (bFGF), PMA at 100 ng/ml completely inhibits bFGF-stimulated DNA synthesis. Under the same growth-inhibitory conditions of PMA addition, aggregation of phosphatidylinositol 3-kinase (PI3K) to the fibroblast growth factor receptor and tyrosine phosphorylation of the 85-kDa regulatory component of the signal transfer protein PI3K are reduced by 94 and 79%, respectively. PI3K catalytic activity, as measured by conversion of phosphatidylinositol to phosphatidylinositol 3-phosphate, is decreased 88% by PMA addition. This effect is not specific to PI3K, since aggregation of phospholipase C-gamma 1 to the activated bFGF receptor is also decreased by PMA treatment. In addition, the PI3K inhibitor wortmannin markedly attenuates bFGF-stimulated VSM cell growth in a dose-dependent manner. These data suggest that the site of growth inhibition by PMA in VSM cells lies upstream of signal transfer particle aggregation and that such growth arrest may be mediated through inhibition of activation of PI3K.

scholarly journals Phosphatidylinositol 3-Kinase/Akt Mediates Integrin Signaling To Control RNA Polymerase I Transcriptional Activity

2016 ◽  
Vol 36 (10) ◽  
pp. 1555-1568 ◽  
Author(s):  
Chuanyue Wu ◽  
Jin You ◽  
Jijun Fu ◽  
Xingshun Wang ◽  
Yandong Zhang
Keyword(s):  
Cell Growth ◽  
Rna Polymerase ◽  
Transcriptional Activity ◽  
Rna Polymerase I ◽  
Integrin Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Rrna Transcription ◽  
Signaling Axis ◽  
Polymerase I ◽  
Phosphatidylinositol 3

RNA polymerase I-mediated rRNA production is a key determinant of cell growth. Despite extensive studies, the signaling pathways that control RNA polymerase I-mediated rRNA production are not well understood. Here we provide original evidence showing that RNA polymerase I transcriptional activity is tightly controlled by integrin signaling. Furthermore, we show that a signaling axis consisting of focal adhesion kinase (FAK), Src, phosphatidylinositol 3-kinase (PI3K), Akt, and mTOR mediates the effect of integrin signaling on rRNA transcription. Additionally, we show that in kindlin-2 knockout mouse embryonic fibroblasts, overactivation of Ras, Akt, and Src can successfully rescue the defective RNA polymerase I activity induced by the loss of kindlin-2. Finally, through experiments with inhibitors of FAK, Src, and PI3K and rescue experiments in MEFs, we found that the FAK/Src/PI3K/Akt signaling pathway to control rRNA transcription is linear. Collectively, these studies reveal, for the first time, a pivotal role of integrin signaling in regulation of RNA polymerase I transcriptional activity and shed light on the downstream signaling axis that participates in regulation of this key aspect of cell growth.

scholarly journals Activation of Phosphatidylinositol 3-Kinase Is Sufficient for Cell Cycle Entry and Promotes Cellular Changes Characteristic of Oncogenic Transformation

1998 ◽  
Vol 18 (10) ◽  
pp. 5699-5711 ◽  
Author(s):  
Anke Klippel ◽  
Maria-Amelia Escobedo ◽  
Matthew S. Wachowicz ◽  
Gerald Apell ◽  
Timothy W. Brown ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Soft Agar ◽  
S Phase ◽  
Oncogenic Transformation ◽  
Phosphatidylinositol 3 Kinase ◽  
Kinase Activation ◽  
Serum Stimulation ◽  
Cellular Changes ◽  
Phosphatidylinositol 3

ABSTRACT Using a new inducible form of phosphatidylinositol 3-kinase (PI 3-kinase) we have found that PI 3-kinase activation has the following effects on cell growth and proliferation. (i) Activation of PI 3-kinase was sufficient to promote entry into S phase of the cell cycle within several hours. This was shown by activation of cyclin-dependent kinase 4 (Cdk4) and Cdk2 and by the induction of DNA synthesis. (ii) PI 3-kinase activation alone was not, however, sufficient to provide for progression through the entire cell cycle. Instead, prolonged activation of PI 3-kinase in the absence of serum stimulation resulted in apoptosis. It is possible that the cells undergo apoptosis because the PI 3-kinase-induced entry into the cell cycle is abnormal. For example, we found that the cyclin E-Cdk2 complex, which normally disappears after entry into S phase of the cell cycle, fails to be downregulated following induction by PI 3-kinase. (iii) Finally, we found that prolonged activation of PI 3-kinase in the presence of serum resulted in cellular changes that resemble those associated with oncogenic transformation. The cells reached high densities, were irregular and refractile in appearance, and formed colonies in soft agar. In contrast, neither PI 3-kinase nor serum stimulation alone could induce these changes. Our results suggest that activation of PI 3-kinase promotes anchorage-independent cell growth and entry into the cell cycle but does not abrogate the growth factor requirement for cell proliferation.

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