Insulin-like growth factor (IGF) binding protein-3 regulation of IGF-I is altered in an acidic extracellular environment.
Insulin-like growth factor (IGF) binding protein-3 regulation of IGF-I is altered in an acidic extracellular environment.
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胰岛素样生长因子 (IGF) 结合蛋白 3 对 IGF-I 的调节在酸性细胞外环境中发生改变。
DOI：
10.1002/jcp.10033
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
SanAntonio,JD
中科院分区：
文献类型：
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作者：
Forsten,KE;Akers,RM;SanAntonio,JD
虽然实体瘤中的细胞外酸化是有据可查的，但pH值降低如何影响胰岛素样生长因子-I（IGF-I）的调节尚未得到广泛研究。由于IGF-I受体结合受IGF结合蛋白（IGFBPs）的影响，我们研究了pH如何影响IGFBP-3对IGF-I的调节。在不存在IGFBP-3的情况下，IGF-I结合在降低的pH下减少。在pH 7.4下，IGFBP-3的添加减少了IGF-I细胞结合，但在pH 5.8下增加了表面结合。在pH 5.8下IGF-I结合的这种增加与IGFBP-3细胞结合的增加相对应。然而，这不是由于在降低的pH下IGFBP-3对肝素的亲和力增加，尽管肝素酶III处理和肝素添加都降低了IGFBP-3对IGF-I结合的增强。然而，使用无细胞测定在降低的pH下观察到IGF-I与IGFBP-3结合的增加。我们假设，在pH 5.8时，IGFBP-3的结合增加促进了IGF-I的结合增强，并且所得的细胞相关IGF-I是IGFBP-3而不是IGF-IR结合。在存在IGFBP-3的情况下，在pH 5.8下IGF-I的内化和核结合增加是明显的，然而在pH 5.8和7.4下IGFBP-3都降低了细胞增殖，表明IGFBP-3-细胞相关的IGF-I不向细胞发出增殖信号，并且所产生的结合的IGF-I从IGF-IR转移到IGFBP-3导致增殖减少。IGFBP-3与IGF-I的溶液结合是抑制IGF-I诱导的增殖的一种方法。我们的工作表明，存在一种替代途径，IGF-I和IGFBP-3都与细胞表面结合，这种结合抑制了IGF-I诱导的增殖。© 2001 Wiley利斯公司
While extracellular acidification within solid tumors is well‐documented, how reduced pH impacts regulation of insulin‐like growth factor‐I (IGF‐I) has not been studied extensively. Because IGF‐I receptor binding is affected by IGF binding proteins (IGFBPs), we examined how pH impacted IGFBP‐3 regulation of IGF‐I. IGF‐I binding in the absence of IGFBP‐3 was diminished at reduced pH. Addition of IGFBP‐3 reduced IGF‐I cell binding at pH 7.4 but increased surface association at pH 5.8. This increase in IGF‐I binding at pH 5.8 corresponded with an increase in IGFBP‐3 cell association. This, however, was not due to an increase in affinity of IGFBP‐3 for heparin at reduced pH although both heparinase III treatment and heparin addition reduced IGFBP‐3 enhancement of IGF‐I binding. An increase in IGF‐I binding to IGFBP‐3, though, was seen at reduced pH using a cell‐free assay. We hypothesize that the enhanced binding of IGF‐I at pH 5.8 is facilitated by increased association of IGFBP‐3 at this pH and that the resulting cell associated IGF‐I is IGFBP‐3 and not IGF‐IR bound. Increased internalization and nuclear association of IGF‐I at pH 5.8 in the presence of IGFBP‐3 was evident, yet cell proliferation was reduced by IGFBP‐3 at both pH 5.8 and 7.4 indicating that IGFBP‐3‐cell associated IGF‐I does not signal the cell to proliferate and that the resulting transfer of bound IGF‐I from IGF‐IR to IGFBP‐3 results in diminished proliferation. Solution binding of IGF‐I by IGFBP‐3 is one means by which IGF‐I‐induced proliferation is inhibited. Our work suggests that an alternative pathway exists by which IGF‐I and IGFBP‐3 both associate with the cell surface and that this association inhibits IGF‐I‐induced proliferation. © 2001 Wiley‐Liss, Inc.