PDGF induces an early and a late wave of PI 3-kinase activity, and only the late wave is required for progression through G1

Jones, Steven M.; Klinghoffer, Richard A.; Prestwich, Glenn D.; Toker, Alex; Kazlauskas, Andrius

doi:10.1016/s0960-9822(99)80235-8

Cited by 141 publications

(153 citation statements)

References 61 publications

(84 reference statements)

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“…B, the solid curve is the model prediction; the only fitted parameter here was a scaling constant for alignment with the data. stimulated PI 3-kinase activation has previously been implicated in the control of different cell responses (37). The kinetics of Akt activation relative to PDGF receptor phosphorylation are completely consistent with saturation at the level of PI 3-kinase activation.…”

Section: Pdgf Receptor Binding Dimerization and Endocytosissupporting

confidence: 67%

“…To examine complexities such as the timing and duration of signal activation, which have been implicated as important factors governing cell function (36,37), a more quantitative approach is warranted. To this end, we have made reasonably precise measurements of PDGF-stimulated activation of the PDGF receptor/PI 3-kinase/Akt signaling pathway in NIH 3T3 fibroblasts, at various times and over a range of PDGF concentrations.…”

mentioning

confidence: 99%

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Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts

Park

Schneider²,

Haugh

2003

Journal of Biological Chemistry

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Isoforms of the serine-threonine kinase Akt coordinate multiple cell survival pathways in response to stimuli such as platelet-derived growth factor (PDGF). Activation of Akt is a multistep process, which relies on the production of 3 -phosphorylated phosphoinositide (PI) lipids by PI 3-kinases. To quantitatively assess the kinetics of PDGF receptor/PI 3-kinase/Akt signaling in fibroblasts, a systematic study of this pathway was performed, and a mechanistic mathematical model that describes its operation was formulated. We find that PDGF receptor phosphorylation exhibits positive cooperativity with respect to PDGF concentration, and its kinetics are quantitatively consistent with a mechanism in which receptor dimerization is initially mediated by the association of two 1:1 PDGF/PDGF receptor complexes. Receptor phosphorylation is transient at high concentrations of PDGF, consistent with the loss of activated receptors upon endocytosis. By comparison, Akt activation responds to lower PDGF concentrations and exhibits more sustained kinetics. Further analysis and modeling suggest that the pathway is saturated at the level of PI 3-kinase activation, and that the p110␣ catalytic subunit of PI 3-kinase contributes most to PDGFstimulated 3 -PI production. Thus, at high concentrations of PDGF the kinetics of 3 -PI production are limited by the turnover rate of these lipids, while the Akt response is additionally influenced by the rate of Akt deactivation.Platelet-derived growth factor (PDGF) 1 is a polypeptide mitogen of broad specificity, one of the earliest and most potent serum factors to be isolated (1). Beyond signaling of proliferation, PDGF acts as a strong chemoattractant during wound healing and can mediate protection from apoptosis in response to serum withdrawal and certain stress stimuli (2, 3). Three forms of PDGF have been studied extensively. They are composed of disulfide-bonded homo-and heterodimers of A and B chains, of which PDGF-BB is the best characterized. There are two structurally related PDGF receptors, ␣ and ␤, which exhibit different affinities for the A chain but roughly equivalent affinities for the B chain (4, 5). More recently, PDGF-C and -D isoforms, which form homodimers, have also been identified; these too exhibit different affinities for PDGF ␣-and ␤-receptors (6 -8).PDGF receptors belong to the well studied class of signal transducers collectively known as receptor-tyrosine kinases (9, 10). As with other receptors of this class, ligand-induced dimerization of PDGF receptors activates their intrinsic kinase domains, which catalyze the autophosphorylation of the receptors on multiple intracellular tyrosine residues in trans (11-13). The phosphorylated receptor may then act as a scaffold for specific binding interactions with cytosolic signal transduction enzymes and adaptor proteins (14). Among the most important of these are isoforms of phosphoinositide (PI) 3-kinase, which phosphorylate phosphatidylinositol (PtdIns) lipids in cell membranes to produce the 3Ј-PI second messengers PtdI...

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Section: Pdgf Receptor Binding Dimerization and Endocytosissupporting

confidence: 67%

mentioning

confidence: 99%

Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts

Park

Schneider²,

Haugh

2003

Journal of Biological Chemistry

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“…Distinct waves of PI3K activation have also been observed in fibroblasts, the second occurring during the G 1 phase several hours after addition of the growth factor (29). Two recent articles used fluorescence microscopy to demonstrate elegantly that Ag-specific T cell activation is accompanied by sustained production of the PI3K lipid product phosphatidylinositol 3,4,5-triphosphate (16,30).…”

Section: Discussionmentioning

confidence: 99%

Proliferation and Survival of Activated B Cells Requires Sustained Antigen Receptor Engagement and Phosphoinositide 3-Kinase Activation

Donahue

Fruman

2003

The Journal of Immunology

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In this study, we investigate the extracellular and intracellular signals that drive cell cycle progression of activated B cells in the absence of T cell help. We find that brief engagement of the B cell receptor is sufficient to induce a single cell division in a fraction of cells, but that survival during successive cell divisions requires sustained receptor stimulation. In contrast, T cells have been shown previously to commit to multiple cell divisions following brief TCR engagement. Both early and late B cell receptor signals are blocked by inhibitors of phosphoinositide 3-kinase and mammalian target of rapamycin and are associated with S6 kinase activation and increased cell size. The requirement for ongoing Ag receptor signaling can be overcome by engagement of CD40 but only partially by IL-4. Proliferation driven by LPS also requires sustained exposure to the stimulus. These findings reveal checkpoints that may limit T-independent B cell responses when Ag exposure is transient.

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“…The PI3-K pathway is activated during two phases of the cell cycle, at first during early G 1 phase and the second wave of PI3-K activity is during late S phase (Jones et al, 1999). Many studies have demonstrated the functional significance of PI3-K activation during G 1 /S transition, but the significance of the second wave of activation is not completely known.…”

Section: Pi3-k/akt Pathway and Cell Cycle Progressionmentioning

confidence: 99%

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

Maddika¹,

Ande²,

Panigrahi³

et al. 2007

Drug Resistance Updates

403

302

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The partial cross-utilization of molecules and pathways involved in opposing processes like cell survival, proliferation and cell death, assures that mutations within one signaling cascade will also affect the other opposite process at least to some extent, thus contributing to homeostatic regulatory circuits. This review highlights some of the connections between opposite-acting pathways. Thus, we discuss the role of cyclins in the apoptotic process, and in the regulation of cell proliferation. CDKs and their inhibitors like the INK4-family (p16 Ink4a , p15 Ink4b , p18 Ink4c , p19 Ink4d ), and the Cip1/Waf1/Kip1-2-family (p21 Cip1/Waf1 , p27 Kip1 , p57 Kip2 ) are shown both in the context of proliferation regulators and as contributors to the apoptotic machinery. Bcl2-family members (i.e. Bcl2, Bcl-X L Mcl-1 L ; Bax, Bok/Mtd, Bak, and Bcl-X S ; Bad, Bid, Bim EL , Bmf, Mcl-1 S ) are highlighted both for their apoptosis-regulating capacity and also for their effect on the cell cycle progression. The PI3-K/Akt cell survival pathway is shown as regulator of cell metabolism and cell survival, but examples are also provided where aberrant activity of the pathway may contribute to the induction of apoptosis. Myc/Mad/Max proteins are shown both as a powerful S-phase driving complex and as apoptosis-sensitizers. We also discuss multifunctional proteins like p53 and Rb (RBL1/p107, RBL2/p130) both in the context of G 1 -S transition and as apoptotic triggers. Finally, we reflect on novel therapeutic approaches that would involve redirecting over-active survival and proliferation pathways towards induction of apoptosis in cancer cells.

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PDGF induces an early and a late wave of PI 3-kinase activity, and only the late wave is required for progression through G1

Abstract: PDGF induces distinct waves of PI 3-kinase activity. The second wave is required for PDGF-dependent DNA synthesis, whereas the initial wave is not. One of the ways in which cells use PI 3-kinase to mediate distinct cellular responses seems to be by regulating when its products accumulate.

Cited by 141 publications

References 61 publications

Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts

Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts

Proliferation and Survival of Activated B Cells Requires Sustained Antigen Receptor Engagement and Phosphoinositide 3-Kinase Activation

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

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