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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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Graphic representation of the potential Ser, Thr, and Tyr residues for phosphorylation and o-glycosylation modification at human IGFBP-6. A) Predicted potential sites for phosphate modification on Ser and Thr residues. The light gray horizontal line indicates the threshold for modification potential. The blue, green and red vertical lines show the potential phosphorylated Ser, Thr and Tyr residues, respectively. B) Predicted potential sites for o-glycosylation modification of Ser and Thr. O-β-GlcNAc modification potential of Ser/Thr residues is shown by green vertical line, while the light blue wavy line indicates the threshold for modification potential. C) The Yin Yang sites that were positively predicted are shown with red asterisk at the top, while the NP-Yin-Yang sites are shown with purple asterisk on the top of vertical lines. The green vertical lines show the O-β-GlcNAc potential of Ser/Thr residue and the light blue horizontal wavy line indicates the threshold for modification potential.
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Figure 2: Graphic representation of the potential Ser, Thr, and Tyr residues for phosphorylation and o-glycosylation modification at human IGFBP-6. A) Predicted potential sites for phosphate modification on Ser and Thr residues. The light gray horizontal line indicates the threshold for modification potential. The blue, green and red vertical lines show the potential phosphorylated Ser, Thr and Tyr residues, respectively. B) Predicted potential sites for o-glycosylation modification of Ser and Thr. O-β-GlcNAc modification potential of Ser/Thr residues is shown by green vertical line, while the light blue wavy line indicates the threshold for modification potential. C) The Yin Yang sites that were positively predicted are shown with red asterisk at the top, while the NP-Yin-Yang sites are shown with purple asterisk on the top of vertical lines. The green vertical lines show the O-β-GlcNAc potential of Ser/Thr residue and the light blue horizontal wavy line indicates the threshold for modification potential.

Mentions: Prediction results by NetPhos 2.0 for possible phosphorylation sites revealed that IGFBP-6 possesses high potential for phosphate modification like other subtypes. 15 phosphorylation sites at Ser, Thr and Tyr residues were predicted. In IGFBP-6 there are 9 Ser, 4 Thr, and 2 Tyr residues that are subjected to phosphorylation as shown in Figure 2.


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)

Graphic representation of the potential Ser, Thr, and Tyr residues for phosphorylation and o-glycosylation modification at human IGFBP-6. A) Predicted potential sites for phosphate modification on Ser and Thr residues. The light gray horizontal line indicates the threshold for modification potential. The blue, green and red vertical lines show the potential phosphorylated Ser, Thr and Tyr residues, respectively. B) Predicted potential sites for o-glycosylation modification of Ser and Thr. O-β-GlcNAc modification potential of Ser/Thr residues is shown by green vertical line, while the light blue wavy line indicates the threshold for modification potential. C) The Yin Yang sites that were positively predicted are shown with red asterisk at the top, while the NP-Yin-Yang sites are shown with purple asterisk on the top of vertical lines. The green vertical lines show the O-β-GlcNAc potential of Ser/Thr residue and the light blue horizontal wavy line indicates the threshold for modification potential.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Graphic representation of the potential Ser, Thr, and Tyr residues for phosphorylation and o-glycosylation modification at human IGFBP-6. A) Predicted potential sites for phosphate modification on Ser and Thr residues. The light gray horizontal line indicates the threshold for modification potential. The blue, green and red vertical lines show the potential phosphorylated Ser, Thr and Tyr residues, respectively. B) Predicted potential sites for o-glycosylation modification of Ser and Thr. O-β-GlcNAc modification potential of Ser/Thr residues is shown by green vertical line, while the light blue wavy line indicates the threshold for modification potential. C) The Yin Yang sites that were positively predicted are shown with red asterisk at the top, while the NP-Yin-Yang sites are shown with purple asterisk on the top of vertical lines. The green vertical lines show the O-β-GlcNAc potential of Ser/Thr residue and the light blue horizontal wavy line indicates the threshold for modification potential.
Mentions: Prediction results by NetPhos 2.0 for possible phosphorylation sites revealed that IGFBP-6 possesses high potential for phosphate modification like other subtypes. 15 phosphorylation sites at Ser, Thr and Tyr residues were predicted. In IGFBP-6 there are 9 Ser, 4 Thr, and 2 Tyr residues that are subjected to phosphorylation as shown in Figure 2.

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