cAMP-GEF cytoprotection by Src tyrosine kinase activation of phosphoinositide-3-kinase p110 β/α in rat hepatocytes

Gates, Anna; Hohenester, Simon; Anwer, M. Sawkat; Webster, Cynthia R. L.

doi:10.1152/ajpgi.90622.2008

Cited by 25 publications

(34 citation statements)

References 65 publications

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“…Such a hypothesis is consistent with the other findings that a) PI3K-Akt pathway is cytoprotective(Gates et al 2009, Rust et al 2005, Webster et al 2002b), b) the cytoprotective effect of cAMP-GEF in hepatocytes is associated with PI3Kp110α/p110β activation (Gates et al 2009), and c) PI3K-p110α is necessary for insulin signaling in the liver(Foukas et al 2006). …”

Section: Signaling Pathways Affected By Bile Acidssupporting

confidence: 91%

“…For example, activation ofp110α is implicated in cell survival (Benistant et al 2000, Gates et al 2009), physiologic cardiac hypertrophy (Pretorius et al 2009), and insulin signaling (Foukas et al 2006). De novo DNA synthesis (Benistant et al 2000) and carcinogenesis (Jia et al 2008) are associated with activation of p110β.…”

Section: Signaling Pathways Affected By Bile Acidsmentioning

confidence: 99%

“…Since then various studies have provided evidence supporting a role for PI3K/Akt pathway in cell survival and translocation of hepatocellular transporters to the plasma membrane, indicating a beneficial role of PI3K in hepatic cells (Anwer 2004, Gates et al 2009, Rust et al 2005, Webster et al 2002b). However, it is now evident that choleretic (TCA and TUDCA) as well as cholestatic (TLCA and TCDCA) bile acids activate PI3K (Beuers et al 2003, Kurz et al 2000, Misra et al 1998, Rust et al 2000).…”

Section: Signaling Pathways Affected By Bile Acidsmentioning

confidence: 99%

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Intracellular Signaling by Bile Acids

Anwer

2014

J bio-sci.

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Bile acids, synthesized from cholesterol, are known to produce beneficial as well as toxic effects in the liver. The beneficial effects include choleresis, immunomodulation, cell survival, while the toxic effects include cholestasis, apoptosis and cellular toxicity. It is believed that bile acids produce many of these effects by activating intracellular signaling pathways. However, it has been a challenge to relate intracellular signaling to specific and at times opposing effects of bile acids. It is becoming evident that bile acids produce different effects by activating different isoforms of phosphoinositide 3-kinase (PI3K), Protein kinase Cs (PKCs), and mitogen activated protein kinases (MAPK). Thus, the apoptotic effect of bile acids may be mediated via PI3K-110γ, while cytoprotection induce by cAMP-GEF pathway involves activation of PI3K-p110α/β isoforms. Atypical PKCζ may mediate beneficial effects and nPKCε may mediate toxic effects, while cPKCα and nPKCδ may be involved in both beneficial and toxic effects of bile acids. The opposing effects of nPKCδ activation may depend on nPKCδ phosphorylation site(s). Activation of ERK1/2 and JNK1/2 pathway appears to mediate beneficial and toxic effects, respectively, of bile acids. Activation of p38α MAPK and p38β MAPK may mediate choleretic and cholestatic effects, respectively, of bile acids. Future studies clarifying the isoform specific effects on bile formation should allow us to define potential therapeutic targets in the treatment of cholestatic disorders.

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Section: Signaling Pathways Affected By Bile Acidssupporting

confidence: 91%

Section: Signaling Pathways Affected By Bile Acidsmentioning

confidence: 99%

Section: Signaling Pathways Affected By Bile Acidsmentioning

confidence: 99%

See 1 more Smart Citation

Intracellular Signaling by Bile Acids

Anwer

2014

J bio-sci.

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“…Since then various studies have provided evidence supporting a role for PI3K/Akt pathway in cell survival and translocation of hepatocellular transporters to the plasma membrane, indicating a beneficial role of PI3K in hepatic cells (4,48,130,160). PI3Ks are a family of lipid kinases (classes I, II, and III) that phosphorylate the inositol ring of phosphatidylinositides (PIs) at 3 position known as D3 phosphorylation (24).…”

Section: Post-translational Regulation Of Ntcp and Asbtmentioning

confidence: 99%

Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters

Anwer

Stieger

2013

Pflugers Arch - Eur J Physiol

Self Cite

129

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Summary The SLC10A transporter gene family consists of seven members and substrates transported by three members (SLC10A1, SLC10A2 and SLC10A6) are Na+-dependent. SLC10A1 (sodium taurocholate cotransporting polypeptide or NTCP) and SLC10A2 (apical sodium-dependent bile salt transporter or ASBT) transport bile salts and play an important role in maintaining enterohepatic circulation of bile salts. Solutes other than bile salts are also transported by NTCP. However, ASBT has not been shown to be a transporter for non-bile salt substrates. While the transport function of NTCP can potentially be used as liver function test, interpretation of such a test may be complicated by altered expression of NTCP in diseases and presence of drugs that may inhibit NTCP function. Transport of bile salts by NTCP and ASBT is inhibited by a number of drugs and it appears that ASBT is more permissive to drug inhibition than NTCP. The clinical significance of this inhibition in drug disposition and drug-drug interaction remains to be determined. Both NCTP and ASBT undergo post-translational regulations that involve phosphorylation/dephosphorylation, translocation to and retrieval from the plasma membrane and degradation by the ubiquitin-proteasome system. These posttranslational regulations are mediated via signaling pathways involving cAMP, calcium, nitric oxide, phosphoinositide-3-kinase (PI3K), protein kinase C (PKC) and protein phosphatases. There appears to be species difference in the substrate specificity and the regulation of plasma membrane localization of human and rodent NTCP. These differences should be taken into account when extrapolating rodent data for human clinical relevance and developing novel therapies. NTCP has recently been shown to play an important role in HBV and HDV infection by serving as a receptor for entry of these viruses into hepatocytes.

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“…It has been reported that the cytoprotective effect of cAMP-GEF in hepatocytes is associated with PI3K p110α/p110β activation (Gates et al, 2009), and p110α is known to be necessary for insulin signaling in the liver (Foukas et al, 2006). Further, Hohenester and colleagues revealed that PI3K p110γ contributes to bile-salt induced apoptosis in hepatocytes (Hohenester et al, 2010).…”

Section: I3 Phosphatidyl-insitol-3-kinase (Pi3k)mentioning

confidence: 99%