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亮氨酸缺乏时IGFBP - 1磷酸化增加是由CK2和蛋白激酶C介导的。

Increased IGFBP-1 phosphorylation in response to leucine deprivation is mediated by CK2 and PKC.

作者信息

Malkani Niyati, Biggar Kyle, Shehab Majida Abu, Li Shawn Shun-Cheng, Jansson Thomas, Gupta Madhulika B

机构信息

Dept of Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.

Children's Health Research Institute, University of Western Ontario, London, ON, Canada.

出版信息

Mol Cell Endocrinol. 2016 Apr 15;425:48-60. doi: 10.1016/j.mce.2015.12.006. Epub 2015 Dec 28.

DOI:10.1016/j.mce.2015.12.006
PMID:26733150
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4811673/
Abstract

Insulin-like growth factor binding protein-1 (IGFBP-1), secreted by fetal liver, is a key regulator of IGF-I bioavailability and fetal growth. IGFBP-1 phosphorylation decreases IGF-I bioavailability and diminishes its growth-promoting effects. Growth-restricted fetuses have decreased levels of circulating essential amino acids. We recently showed that IGFBP-1 hyperphosphorylation (pSer101/119/169) in response to leucine deprivation is regulated via activation of the amino acid response (AAR) in HepG2 cells. Here we investigated nutrient-sensitive protein kinases CK2/PKC/PKA in mediating IGFBP-1 phosphorylation in leucine deprivation. We demonstrated that leucine deprivation stimulated CK2 activity (enzymatic assay) and induced IGFBP-1 phosphorylation (immunoblotting/MRM-MS). Inhibition (pharmacological/siRNA) of CK2/PKC, but not PKA, prevented IGFBP-1 hyperphosphorylation in leucine deprivation. PKC inhibition also prevented leucine deprivation-stimulated CK2 activity. Functionally, leucine deprivation decreased IGF-I-induced-IGF-1R autophosphorylation when CK2/PKC were not inhibited. Our data strongly support that PKC promotes leucine deprivation-induced IGFBP-1 hyperphosphorylation via CK2 activation, mechanistically linking decreased amino acid availability and reduced fetal growth.

摘要

胰岛素样生长因子结合蛋白-1（IGFBP-1）由胎儿肝脏分泌，是IGF-I生物利用度和胎儿生长的关键调节因子。IGFBP-1磷酸化会降低IGF-I生物利用度并减弱其促生长作用。生长受限胎儿的循环必需氨基酸水平降低。我们最近发现，在HepG2细胞中，亮氨酸缺乏时IGFBP-1的过度磷酸化（pSer101/119/169）是通过氨基酸反应（AAR）的激活来调节的。在此，我们研究了营养敏感蛋白激酶CK2/PKC/PKA在亮氨酸缺乏介导的IGFBP-1磷酸化中的作用。我们证明，亮氨酸缺乏会刺激CK2活性（酶活性测定）并诱导IGFBP-1磷酸化（免疫印迹/MRM-MS）。抑制CK2/PKC（通过药理学方法/小干扰RNA），而非PKA，可防止亮氨酸缺乏时IGFBP-1的过度磷酸化。PKC抑制也可防止亮氨酸缺乏刺激的CK2活性。在功能上，当CK2/PKC未被抑制时，亮氨酸缺乏会降低IGF-I诱导的IGF-1R自身磷酸化。我们的数据有力地支持，PKC通过激活CK2促进亮氨酸缺乏诱导的IGFBP-1过度磷酸化，从机制上连接了氨基酸可利用性降低与胎儿生长减少之间的关系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/6a348776555d/nihms-758762-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/e5aba2151d74/nihms-758762-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/b8ea67231e7c/nihms-758762-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/822f4c543e09/nihms-758762-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/8f9e6f6d5602/nihms-758762-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/3ad81d012c01/nihms-758762-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/6a348776555d/nihms-758762-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/e5aba2151d74/nihms-758762-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/6b31443e37e8/nihms-758762-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/c04361100479/nihms-758762-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/b8ea67231e7c/nihms-758762-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/822f4c543e09/nihms-758762-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/8f9e6f6d5602/nihms-758762-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/3ad81d012c01/nihms-758762-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b787/4811673/6a348776555d/nihms-758762-f0010.jpg

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胰岛素样生长因子结合蛋白-1磷酸化在胎儿生长受限中的作用及调控
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