p85 regulatory subunit of PI3K mediates cAMP–PKA and estrogens biological effects on growth and survival

Cosentino, Claudia; Domenico, Marina Di; Porcellini, Antonio; Cuozzo, Concetta; Gregorio, G. de; Santillo, Mariarosaria; Secondo, Agnese; Stasio, R Di; Feliciello, Antonio; Migliaccio, Antimo; Avvedimento, Enrico V.

doi:10.1038/sj.onc.1210027

Cited by 69 publications

(78 citation statements)

References 24 publications

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“…This is a non-redundant circuit in thyroid or cells expressing TSHR and PKAIIb, because its elimination profoundly impaired survival and growth. In contrast, in cells containing low levels of cAMP and RIIb, the expression of p85A abolished only cAMP response, with a marginal effect on survival (data not shown; Cosentino et al, 2006). As for the mechanism, the data presented indicate that the serine 83 in p85a PI3K is a critical site for the transmission of receptor signals to PI3K.…”

Section: Discussionmentioning

confidence: 79%

“…Mutagenesis of this site profoundly and selectively impaired the transmission of TSH signals by disrupting this complex. EGF (Supplementary Figure 2S and Figure 6) or PDGF stimulation of PI3K (Cosentino et al, 2006) was not influenced by the substitution of serine 83 by alanine or aspartate in p85a PI3K . The stimulation of PI3K catalytic activity by cAMP-TSH was evident in the absence of serum (see also, Porcellini et al, 2003) and was dependent on the phosphorylation of serine 83 in p85a PI3K .…”

Section: Discussionmentioning

confidence: 93%

“…It is possible that a conformational change induced by phosphorylation is important for stimulation of PI3K activity. It is noteworthy that substitution of serine 83 by aspartate in p85a PI3K stabilizes the complex with p110 (Cosentino et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…To verify that this sequence was a bona fide PKA site, we have substituted this serine 83 by alanine (p85A) or aspartate (p85D) to prevent or to mimic phosphorylation of serine, respectively. The tagged wild-type recombinant protein was phosphorylated in vivo and in vitro by PKA, whereas p85A protein was not (Cosentino et al, 2006).…”

Section: P85 Phosphorylation Mediates Tsh-dependent Cell Cycle Progrementioning

confidence: 99%

“…This phosphorylation mediates the interaction of PI3K with p21Ras and estrogen receptor a (Cosentino et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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The p85 regulatory subunit of PI3K mediates TSH–cAMP–PKA growth and survival signals

et al. 2006

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Phosphatidylinositol 3-kinase (PI3K) is necessary for thyroid stimulating hormone (TSH)-induced cell cycle progression. To determine the molecular mechanism linking PI3K to TSH, we have identified a serine residue in p85a PI3K phosphorylated by protein kinase A (PKA) in vitro and in vivo. Expression of an alanine mutant (p85A) abolished cyclic AMP/TSH-induced cell cycle progression and was lethal in thyroid cells . The aspartic version of the p85a PI3K (p85D) inhibited apoptosis following TSH withdrawal. The p85a PI3K wild type not the p85A bound PKA regulatory subunit RIIb in cells stimulated with cAMP or TSH. The binding of the aspartic version of p85a PI3K to RIIb was independent of cAMP or TSH stimulation. Similarly, binding of PI3K to p21Ras and activation of AKT, a downstream PI3K target, were severely impaired in cells expressing the p85A mutant. Finally, we found that the catalytic activity of PI3K was stimulated by TSH in cells expressing the wildtype p85a PI3K but not in cells expressing p85A. This latter mutant did not affect the epidermal growth factorstimulated PI3K activity. We suggest that (1) TSHcAMP-induced PKA phosphorylates p85a PI3K at serine 83, (2) phosphorylated p85a PI3K binds RIIb-PKA and targets PKAII to the membrane, and (3) PI3K activity and p21Ras binding to PI3K increase and activate PI3K downstream targets. This pathway is essential for the transmission of TSH-cAMP growth signals.

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Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: P85 Phosphorylation Mediates Tsh-dependent Cell Cycle Progrementioning

confidence: 99%

“…This phosphorylation mediates the interaction of PI3K with p21Ras and estrogen receptor a (Cosentino et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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The p85 regulatory subunit of PI3K mediates TSH–cAMP–PKA growth and survival signals

et al. 2006

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Retracted: Norepinephrine induces VEGF expression and angiogenesis by a hypoxia‐inducible factor‐1α protein‐dependent mechanism

Park

Kang

Jeong

et al. 2010

Intl Journal of Cancer

129

113

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A growing number of studies have demonstrated that physiological factors can influence the progression of several cancers via cellular immune function, angiogenesis and metastasis. Recently, stress-induced catecholamines have been shown to increase the expression of various cancer progressive factors, including vascular endothelial growth factor (VEGF), matrix metalloproteinases and interleukins. However, a detailed mechanism remains to be identified. In this study, we investigated the role of adrenergic receptors and hypoxia-inducible factor (HIF)-1a protein in catecholamine-induced VEGF expression and angiogenesis. Treatment of the cells with norepinephrine (NE) or isoproterenol induced VEGF expression and HIF-1a protein amount in a dose-dependent manner. Induction of VEGF expression by NE was abrogated when the cells were transfected with HIF-1a-specific siRNA. Similarly, adenylate cyclase activator forskolin and cyclic AMP-dependent protein kinase A inhibitor H-89 enhanced and decreased HIF-1a protein amount, respectively. More importantly, conditioned medium of NE-stimulated cancer cells induced angiogenesis in a HIF-1a protein-dependent manner. In addition, pretreatment of cells with propranolol, a b-adrenergic receptor (AR) blocker, completely abolished induction of VEGF expression and HIF-1a protein amount by NE in all of the tested cancer cells. However, treatment with the a1-AR blocker prazosin inhibited NE-induced HIF-1a protein amount and angiogenesis in SK-Hep1 and PC-3 but not MDA-MB-231 cells. Collectively, our results suggest that ARs and HIF-1a protein have critical roles in NE-induced VEGF expression in cancer cells, leading to stimulation of angiogenesis. These findings will help to understand the mechanism of cancer progression by stress-induced catecholamines and design therapeutic strategies for cancer angiogenesis.Researchers have shown that stress and other behavioral conditions are involved in cancer progression.

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The inhibition of p85αPI3KSer83 phosphorylation prevents cell proliferation and invasion in prostate cancer cells

Feola

Cimini

Migliucci

et al. 2013

J of Cellular Biochemistry

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Phosphoinositide 3-kinase proteins are composed by a catalytic p110 subunit and a regulatory p85 subunit. There are three classes of PI3K, named class I-III, on the bases of the protein domain constituting and determining their specificity. The first one is the best characterized and includes a number of key elements for the integration of different cellular signals. Regulatory p85 subunit shares with the catalytic p110 subunit, a N-terminal SH3 domain showing homology with the protein domain Rho-GTP-ase. After cell stimulation, all class I PI3Ks are recruited to the inner face of the plasma membrane, where they generate phosphatidylinositol-3,4,5-trisphosphate by direct phosphorylation of phosphatidylinositol-4,5-bisphosphate. All pathways trigger the control of different phenomena such as cell growth, proliferation, apoptosis, adhesion and migration through various downstream effectors. We have previously provided direct evidences that a Serine in position 83, adjacent to the N-terminal SH3 domain of regulatory subunit of PI3K, is a substrate of PKA. The aim of this work is to confirm the role of p85αPI3KSer83 in regulating cell proliferation, migration and invasion in prostate cancer cells LNCaP. To this purpose cells were transfected with mutant forms of p85, where Serine was replaced by Alanine, where phosphorylation is prevented, or Aspartic Acid, to mimic the phosphorylated residue. The findings of this study suggest that identifying a peptide mimicking the sequence adjacent to Ser 83 may be used to produce antibodies against this residue that can be proposed as usefool tool for prognosis by correlating phosphorylation at Ser83 with tumor stage.

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p85 regulatory subunit of PI3K mediates cAMP–PKA and estrogens biological effects on growth and survival

Cited by 69 publications

References 24 publications

The p85 regulatory subunit of PI3K mediates TSH–cAMP–PKA growth and survival signals

The p85 regulatory subunit of PI3K mediates TSH–cAMP–PKA growth and survival signals

Retracted: Norepinephrine induces VEGF expression and angiogenesis by a hypoxia‐inducible factor‐1α protein‐dependent mechanism

The inhibition of p85αPI3KSer83 phosphorylation prevents cell proliferation and invasion in prostate cancer cells

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