C-Peptides

C-Peptides
Angiogenin (renamed Angiogenin-1; abbr. ANG or Ang-1) is a basic heparin binding protein. Angiogenin is a potent inducer of angiogenesis.

Discovery
The first human tumor derived protein with in vivo angiogenic activity to be obtained in pure form has been isolated from serum-free supernatants of an established human adenocarcinoma cell line (HT-29) and named angiogenin, based solely on its angiogenic activity on the chicken chorioallantoic membrane. It was purified by cation-exchange and reversed-phase high-performance liquid chromatography; the yield was approximately 0.5 microgram/L of medium 1. It actually is a constituent of human plasma2, 3 and normally circulates at a concentration of 250 to 360 ng/ml.

Structural Characteristics
Bovine ANG is a single-chain protein of 125 amino acids; it contains six cysteines and has a calculated molecular weight of 14 kDa. In contrast to the human protein its amino terminus is unblocked. Bovine angiogenin is 64% identical with human angiogenin; like the human protein, it is homologous to the pancreatic ribonucleases, with conservation of active site residues. Two regions, 6-22 and 65-75, are highly conserved between the angiogenins but are significantly different from those of the ribonucleases, suggesting a possible role in the molecules' biological activity 4.

Mode of Action
ANG is a member of the ribonuclease (RNase) superfamily: enzymes of innate substrate specificity, but divergent functional capacities, where angiogenesis is commonly attributed to ANG. Its distinct structure gives angiogenin an endothelial binding motif, which it combines with its endonuclease enzyme activity to produce a potent stimulus for blood vessel formation. Phyisiologically, ANG is induced during inflammation, exhibiting wound healing properties as well as microbicidal activity and conferring host immunity. Interestingly, this protein commonly circulates at markedly high levels in human serum, without a proliferative impact 5.

Functions
ANG activates Erk1/2 in human umbilical vein endothelial cells: ANG is a potent angiogenic factor that induces transient phosphorylation of extracellular signal-related kinase1/2 (Erk1/2) in cultured human umbilical vein endothelial cells. Furthermore, ANG does not affect the phosphorylation status of stress-associated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 mitogen-activated protein (MAP) kinases. PD98059--a specific inhibitor of MAP or Erk kinase 1 (MEK 1), the upstream kinase that phosphorylates Erk1/2--abolishes angiogenin-induced Erk phosphorylation and cell proliferation without affecting nuclear translocation of angiogenin. In contrast, neomycin, a known inhibitor of nuclear translocation and cell proliferation, does not interfere with ANG-induced Erk1/2 phosphorylation. These results indicate that both intracellular signaling pathways and direct nuclear functions of ANG are required for angiogenin-induced cell proliferation and angiogenesis 6.

Increased ANG expression in pancreatic cancer is related to cancer aggressiveness: In a study the expression of ANG in pancreatic cancer and the relevance of ANG expression to the progression of pancreatic cancer were investigated. It was found that in comparison to normal pancreas, increased ANG mRNA expression was observed in 80.0% of the cases of pancreatic cancer by in situ hybridization and Western blot analysis. Furthermore, the mean serum ANG concentration of pancreatic cancer patients (566.6 +/- 191.9 ng/ml) was significantly higher (P <>

Interaction of human ANG with copper modulates ANG binding to endothelial cells: ANG is a potent inducer of blood-vessel formation with ribonucleolytic activity. ANG binds to high affinity endothelial cell receptors and with lower affinity to extracellular matrix components. A study reported the effect of copper and zinc on these interactions. There is evidence that there was a 4.3-fold increase in ANG binding to calf pulmonary artery endothelial cells in the presence of Cu2+ in vitro. A 3.8-fold increase was observed with Zn2+, whereas Ni2+, Co2+, or Li+ had no effect. Specific angiogenin binding to the lower affinity matrix sites was increased by 2.7- and 1.9-fold in the presence of Cu2+ and Zn2+ respectively. ANG bound 2.4 mol of copper per mole of protein. Thus, these results suggest that copper, a modulator of angiogenesis in vivo, may be involved in the regulation of the biological activity of angiogenin7.
References

1. Fett JW, Strydom DJ, Lobb RR, Alderman EM, Bethune JL, Riordan JF, Vallee BL (1985). Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells. Biochemistry., 24(20):5480-5486.
2. Shimoyama S, Gansauge F, Gansauge S, Negri G, Oohara T, Beger HG (1996). Increased angiogenin expression in pancreatic cancer is related to cancer aggressiveness. Cancer. Res., 56(12):2703-2706.
3. Bläser J, Triebel S, Kopp C, Tschesche H (1993). A highly sensitive immunoenzymometric assay for the determination of angiogenin. Eur J. Clin. Chem Clin Biochem., 31(8):513-516.
4. Bond MD, Strydom DJ (1989). Amino acid sequence of bovine angiogenin. Biochemistry, 28(14):6110-6113.
5. Tello-Montoliu A, Patel JV, Lip GYH (2006). Angiogenin: a review of the pathophysiology and potential clinical applications. J. Thromb. Haemost., 4: 864-874.
6. Liu S, Yu D, Xu ZP, Riordan JF, Hu GF (2001). Angiogenin activates Erk1/2 in human umbilical vein endothelial cells. Biochem. Biophys. Res. Commun., 287(1):305-310.
7. Soncin F, Guitton JD, Cartwright T, Badet J (1997). Interaction of human angiogenin with copper modulates angiogenin binding to endothelial cells. Biochem Biophys Res Commun., 236(3):604-610.

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