Identification of carboxypeptidase N as an enzyme responsible for C-terminal cleavage of stromal cell-derived factor-1α in the circulation

被引:82
作者
Davis, DA
Singer, KE
Sierra, MD
Narazaki, M
Yang, FQ
Fales, HM
Yarchoan, R
Tosato, G
机构
[1] NCI, HIV & AIDS Malignancy Branch, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA
[2] NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA
关键词
D O I
10.1182/blood-2004-12-4618
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The chemokine stromal-derived factor-1 alpha (SDF-1 alpha) is an essential regulator of hematopoiesis, lymphocyte homing, pre-B-cell growth, and angiogenesis. As SDF-1 alpha is constitutively expressed in many tissues, chemokine function is mostly regulated by proteolytic degradation. Human serum cleaves the 68-amino acid chemokine, SDF-1 alpha, at both termini. The enzyme or enzymes responsible for the removal of the carboxy-terminal lysine from SDF-1 alpha, leading to significant reduction in biologic activity, have not been identified. Using a new biochemical assay for measuring the carboxy-terminal cleavage activity, we purified from serum and plasma a peptidase that specifically removes the carboxy-terminal lysine from SDF-1 alpha and identified it as carboxypeptidase N (CPN, also known as kininase 1, arginine carboxypeptidase, and anaphylotoxin inactivator). We demonstrate that SDF-1 alpha in serum and plasma lacks the carboxy terminal lysine, and depletion of CPN from serum and plasma significantly reduces the SDF-1 alpha carboxylpeptidase activity. Purified CPN effectively and specifically removes the carboxy-terminal lysine from SDF-1 alpha and significantly reduces the chemokine's biologic activity as a pre-B-cell growth factor and chemoattractant. Thus, in addition to its role as a regulator of the biologic activity of kinins and anaphylatoxins, CPN is an important regulator of the biologic activity of SDF-1 alpha, by reducing the chemokine-specific activity. (c) 2005 by The American Society of Hematology.
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页码:4561 / 4568
页数:8
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