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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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A homology model of human IGFBP-6 utilizing automated protein modeling option was retrieved through I-TASSER server. Five models were received from the server utilizing five different templates namely: model 1-5 through this option. Among the five, one that covered all amino acids with alpha helix structure and beta pleated sheet, high resemblance with experimentally determined C-terminal and high C-value was selected. This model shows that predicted Yin Yang sites have high surface accessibility for the phosphorylation and O-β-GlcNAc interplay. The Ser and Thr residues are denoted by red and green colors respectively.
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Figure 3: A homology model of human IGFBP-6 utilizing automated protein modeling option was retrieved through I-TASSER server. Five models were received from the server utilizing five different templates namely: model 1-5 through this option. Among the five, one that covered all amino acids with alpha helix structure and beta pleated sheet, high resemblance with experimentally determined C-terminal and high C-value was selected. This model shows that predicted Yin Yang sites have high surface accessibility for the phosphorylation and O-β-GlcNAc interplay. The Ser and Thr residues are denoted by red and green colors respectively.

Mentions: Ser residues in the mid region of the IGFBP-6 are the main target of the phosphorylation. Headey et al (2004) found that the IGF-II binding site is located on C-terminal of IGFBP-6 from Leu 174, Gly 206 [21]. Regulation of IGF bioavailability, binding of IGFs to IGFBPs is modulated by phosphorylation process [22]. Phosphorylation of human IGFBPs enhances both its affinity for IGFs and their capacity to inhibit IGFs actions [50]. A phosphorylation site of IGFBP-6 at Thr-126 is described by Baxter and Firth which is phosphorylated by enzyme PKCc and it is also a Yin Yang site [51]. Our Netphos 1.0 and Disphos results showed that IGFBP-6 has high potential for phosphorylation at middle and C-terminal region. As C-terminal of IGFBP-6 is involved as binding site for IGF-II, we found that Ser 204 has high potential for phosphorylation. It was also a conserved residue. Our results of NetPhos K 1.0 and Kinasephos for the prediction of phosphorylation potential of all Ser and Thr residues showed that these residues are phosphorylated by different kinases during cell cycle as shown in Table 2. These experimentally verified residues are conserved in IGFBP-6 and we can assume that these phosphorylated sites may be present on IGFBP-6 of other mammals "by similarity" where these phosphorylation sites are not yet experimentally known. O-β-GlcNAc modification can occur on these Ser and Thr residues where kinases are involved in phosphorylation as it is well known that kinases and OGT can compete for same site modification [34-37,52]. This shows a possibility for interplay between phosphorylation and OGT on these residues. O-glycosylation is known and experimentally verified post-translational modification in IGFBP-6 [53]. YinOYang 1.2 and OGPET prediction results had shown that IGFBP-6 have high potential for O-linked glycosylation (Figure 3).


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)

A homology model of human IGFBP-6 utilizing automated protein modeling option was retrieved through I-TASSER server. Five models were received from the server utilizing five different templates namely: model 1-5 through this option. Among the five, one that covered all amino acids with alpha helix structure and beta pleated sheet, high resemblance with experimentally determined C-terminal and high C-value was selected. This model shows that predicted Yin Yang sites have high surface accessibility for the phosphorylation and O-β-GlcNAc interplay. The Ser and Thr residues are denoted by red and green colors respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: A homology model of human IGFBP-6 utilizing automated protein modeling option was retrieved through I-TASSER server. Five models were received from the server utilizing five different templates namely: model 1-5 through this option. Among the five, one that covered all amino acids with alpha helix structure and beta pleated sheet, high resemblance with experimentally determined C-terminal and high C-value was selected. This model shows that predicted Yin Yang sites have high surface accessibility for the phosphorylation and O-β-GlcNAc interplay. The Ser and Thr residues are denoted by red and green colors respectively.
Mentions: Ser residues in the mid region of the IGFBP-6 are the main target of the phosphorylation. Headey et al (2004) found that the IGF-II binding site is located on C-terminal of IGFBP-6 from Leu 174, Gly 206 [21]. Regulation of IGF bioavailability, binding of IGFs to IGFBPs is modulated by phosphorylation process [22]. Phosphorylation of human IGFBPs enhances both its affinity for IGFs and their capacity to inhibit IGFs actions [50]. A phosphorylation site of IGFBP-6 at Thr-126 is described by Baxter and Firth which is phosphorylated by enzyme PKCc and it is also a Yin Yang site [51]. Our Netphos 1.0 and Disphos results showed that IGFBP-6 has high potential for phosphorylation at middle and C-terminal region. As C-terminal of IGFBP-6 is involved as binding site for IGF-II, we found that Ser 204 has high potential for phosphorylation. It was also a conserved residue. Our results of NetPhos K 1.0 and Kinasephos for the prediction of phosphorylation potential of all Ser and Thr residues showed that these residues are phosphorylated by different kinases during cell cycle as shown in Table 2. These experimentally verified residues are conserved in IGFBP-6 and we can assume that these phosphorylated sites may be present on IGFBP-6 of other mammals "by similarity" where these phosphorylation sites are not yet experimentally known. O-β-GlcNAc modification can occur on these Ser and Thr residues where kinases are involved in phosphorylation as it is well known that kinases and OGT can compete for same site modification [34-37,52]. This shows a possibility for interplay between phosphorylation and OGT on these residues. O-glycosylation is known and experimentally verified post-translational modification in IGFBP-6 [53]. YinOYang 1.2 and OGPET prediction results had shown that IGFBP-6 have high potential for O-linked glycosylation (Figure 3).

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