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Serine 204 phosphorylation and O-β-GlcNAC interplay of IGFBP-6 as therapeutic indicator to regulate IGF-II functions in viral mediated hepatocellular carcinoma.

Ahmad W, Shabbiri K, Ijaz B, Asad S, Nazar N, Nazar S, Fouzia K, Kausar H, Gull S, Sarwar MT, Shahid I, Hassan S - Virol. J. (2011)

Bottom Line: In HCV, core protein is believed to trans-activate host IGF-II receptor through PKC pathway and the inhibition of tumor cell growth can be achieved by blocking IGF-II pathway either at transcriptional level or increasing its binding with IGFBPs (Insulin like growth factor proteins) at C-terminal, so that it is not available in free form.IGFBP-6 is a specific inhibitor of IGF-II actions.Phosphorylation of IGFBPs inhibits IGFs action on target cells while O-glycosylation prevents binding of IGFBP-6 to glycosaminoglycans and cell membranes and resulting in a 10-fold higher affinity for IGF-II.

View Article: PubMed Central - HTML - PubMed

Affiliation: Applied and Functional Genomics Lab, Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.

ABSTRACT
Hepatocellular carcinoma is mainly associated with viral hepatitis B and C. Activation of cell growth stimulator IGF-II gene is observed in tumor formation especially in viral associated hepatocellular carcinoma. Elevated IGF-II levels are indicator of increased risk for cholangiocellular and hepatocellular carcinomas through over saturation of IGF-II binding capacities with IGF receptors leading to cellular dedifferentiation. In HCV, core protein is believed to trans-activate host IGF-II receptor through PKC pathway and the inhibition of tumor cell growth can be achieved by blocking IGF-II pathway either at transcriptional level or increasing its binding with IGFBPs (Insulin like growth factor proteins) at C-terminal, so that it is not available in free form. IGFBP-6 is a specific inhibitor of IGF-II actions. Affinity of IGFBPs with IGFs is controlled by post-translational modifications. Phosphorylation of IGFBPs inhibits IGFs action on target cells while O-glycosylation prevents binding of IGFBP-6 to glycosaminoglycans and cell membranes and resulting in a 10-fold higher affinity for IGF-II. O-glycosylation and phosphorylation operate the functional expression of cellular proteins, this switching on and off the protein expression is difficult to monitor in vivo. By using neural network based prediction methods, we propose that alternate O-β-GlcNAc modification and phosphorylation on Ser 204 control the binding of IGFBP-6 with IGF-II. This information may be used for developing new therapies by regulating IGFBP-6 assembly with IGF-II to minimize the risk of viral associated hepatocellular carcinoma. We can conclude that during HCV/HBV infection, O-β-GlcNAc of IGFBP-6 at Ser 204 diminish their binding with IGF-II, increase IGF-II cellular expression and promote cancer progression which can lead to hepatocellular carcinoma. Furthermore, this site can be used for developing new therapies to control the IGF-II actions during viral infection to minimize the risk of hepatocellular carcinoma.

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Schematic diagram illustrating the role of IGFBP-6 phosphorylation and O-glycosylation on IGF-II functions. Here we propose that alternative O-β-GlcNAc modification and phosphorylation of Ser 204 control the binding of IGF-II with IGFBP-6 during viral infection, while mid region phosphorylation and O-β-GlcNAc modifications controls it's binding with glycosaminoglycans.
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Figure 4: Schematic diagram illustrating the role of IGFBP-6 phosphorylation and O-glycosylation on IGF-II functions. Here we propose that alternative O-β-GlcNAc modification and phosphorylation of Ser 204 control the binding of IGF-II with IGFBP-6 during viral infection, while mid region phosphorylation and O-β-GlcNAc modifications controls it's binding with glycosaminoglycans.

Mentions: As we know that there is competition between O-glycosylation and phosphorylation on Ser and Thr residues [57], we therefore, propose that O-β-GlcNAc and phosphate modifications at Ser 204 residue control the binding of IGFBP-6 with IGF-II, while O-glycosylation and phosphorylation on middle region Ser and Thr residues control the binding of IGFBP-6 with glycosaminoglycans. Since IGFBP-6 has shown an inhibitory effect on IGF functions in many cancer cell lines for example in human breast cancer, so reduced IGFBP-6 levels can therefore, affect cell growth in multiple ways, such as increasing IGF bioavailability and reducing IGF independent growth inhibitory effects etc. So we can conclude that due to O-β-GlcNAc modification at Ser 204, binding of IGFBP-6 with IGF-II reduced and resulting in binding of IGF-II with IGF-II receptor and promote cancer progression which can lead to hepatocellular carcinoma in HCV infected patients (Figure 4). The application of such predictive techniques may be of interest to develop therapeutics to decrease the hepatocellular carcinoma in cases with HCV and HBV-related chronic hepatitis.


Serine 204 phosphorylation and O-β-GlcNAC interplay of IGFBP-6 as therapeutic indicator to regulate IGF-II functions in viral mediated hepatocellular carcinoma.

Ahmad W, Shabbiri K, Ijaz B, Asad S, Nazar N, Nazar S, Fouzia K, Kausar H, Gull S, Sarwar MT, Shahid I, Hassan S - Virol. J. (2011)

Schematic diagram illustrating the role of IGFBP-6 phosphorylation and O-glycosylation on IGF-II functions. Here we propose that alternative O-β-GlcNAc modification and phosphorylation of Ser 204 control the binding of IGF-II with IGFBP-6 during viral infection, while mid region phosphorylation and O-β-GlcNAc modifications controls it's binding with glycosaminoglycans.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108323&req=5

Figure 4: Schematic diagram illustrating the role of IGFBP-6 phosphorylation and O-glycosylation on IGF-II functions. Here we propose that alternative O-β-GlcNAc modification and phosphorylation of Ser 204 control the binding of IGF-II with IGFBP-6 during viral infection, while mid region phosphorylation and O-β-GlcNAc modifications controls it's binding with glycosaminoglycans.
Mentions: As we know that there is competition between O-glycosylation and phosphorylation on Ser and Thr residues [57], we therefore, propose that O-β-GlcNAc and phosphate modifications at Ser 204 residue control the binding of IGFBP-6 with IGF-II, while O-glycosylation and phosphorylation on middle region Ser and Thr residues control the binding of IGFBP-6 with glycosaminoglycans. Since IGFBP-6 has shown an inhibitory effect on IGF functions in many cancer cell lines for example in human breast cancer, so reduced IGFBP-6 levels can therefore, affect cell growth in multiple ways, such as increasing IGF bioavailability and reducing IGF independent growth inhibitory effects etc. So we can conclude that due to O-β-GlcNAc modification at Ser 204, binding of IGFBP-6 with IGF-II reduced and resulting in binding of IGF-II with IGF-II receptor and promote cancer progression which can lead to hepatocellular carcinoma in HCV infected patients (Figure 4). The application of such predictive techniques may be of interest to develop therapeutics to decrease the hepatocellular carcinoma in cases with HCV and HBV-related chronic hepatitis.

Bottom Line: In HCV, core protein is believed to trans-activate host IGF-II receptor through PKC pathway and the inhibition of tumor cell growth can be achieved by blocking IGF-II pathway either at transcriptional level or increasing its binding with IGFBPs (Insulin like growth factor proteins) at C-terminal, so that it is not available in free form.IGFBP-6 is a specific inhibitor of IGF-II actions.Phosphorylation of IGFBPs inhibits IGFs action on target cells while O-glycosylation prevents binding of IGFBP-6 to glycosaminoglycans and cell membranes and resulting in a 10-fold higher affinity for IGF-II.

View Article: PubMed Central - HTML - PubMed

Affiliation: Applied and Functional Genomics Lab, Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.

ABSTRACT
Hepatocellular carcinoma is mainly associated with viral hepatitis B and C. Activation of cell growth stimulator IGF-II gene is observed in tumor formation especially in viral associated hepatocellular carcinoma. Elevated IGF-II levels are indicator of increased risk for cholangiocellular and hepatocellular carcinomas through over saturation of IGF-II binding capacities with IGF receptors leading to cellular dedifferentiation. In HCV, core protein is believed to trans-activate host IGF-II receptor through PKC pathway and the inhibition of tumor cell growth can be achieved by blocking IGF-II pathway either at transcriptional level or increasing its binding with IGFBPs (Insulin like growth factor proteins) at C-terminal, so that it is not available in free form. IGFBP-6 is a specific inhibitor of IGF-II actions. Affinity of IGFBPs with IGFs is controlled by post-translational modifications. Phosphorylation of IGFBPs inhibits IGFs action on target cells while O-glycosylation prevents binding of IGFBP-6 to glycosaminoglycans and cell membranes and resulting in a 10-fold higher affinity for IGF-II. O-glycosylation and phosphorylation operate the functional expression of cellular proteins, this switching on and off the protein expression is difficult to monitor in vivo. By using neural network based prediction methods, we propose that alternate O-β-GlcNAc modification and phosphorylation on Ser 204 control the binding of IGFBP-6 with IGF-II. This information may be used for developing new therapies by regulating IGFBP-6 assembly with IGF-II to minimize the risk of viral associated hepatocellular carcinoma. We can conclude that during HCV/HBV infection, O-β-GlcNAc of IGFBP-6 at Ser 204 diminish their binding with IGF-II, increase IGF-II cellular expression and promote cancer progression which can lead to hepatocellular carcinoma. Furthermore, this site can be used for developing new therapies to control the IGF-II actions during viral infection to minimize the risk of hepatocellular carcinoma.

Show MeSH
Related in: MedlinePlus