PKCα and PKCδ regulate ADAM17-mediated ectodomain shedding of heparin binding-EGF through separate pathways.
PKCα and PKCδ regulate ADAM17-mediated ectodomain shedding of heparin binding-EGF through separate pathways.
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DOI：
10.1371/journal.pone.0017168
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发表时间：
2011-02-28
期刊：
影响因子：
3.7
通讯作者：
Parker PJ
中科院分区：
文献类型：
--
作者：
Kveiborg M;Instrell R;Rowlands C;Howell M;Parker PJ
表皮生长因子受体（EGFR）信号是由EGFR配体从膜锚定的前体释放而启动的，这一过程被称为外膜结构域脱落。这一蛋白水解事件主要由A分解素和金属蛋白酶（ADAMs）执行，受多种信号转导途径调控，其中最显著的是与蛋白激酶C （PKC）有关的信号转导途径。然而，PKC依赖的egfr配体外结构域脱落的分子机制，包括特定PKC异构体的参与和可能的功能冗余，尚不清楚。为了解决这个问题，我们采用了一种基于pma诱导的PKC激活与肝素结合(HB)-EGF脱落的细胞系统。与之前的研究一致，我们证明PMA触发了adam17介导的HB-EGF的快速释放。然而，pma处理也会导致蛋白酶无关的细胞表面HB-EGF的丢失。我们发现PKCα是ADAM17激活的关键参与者，并表明它与连接PKCδ和ERK活性的途径平行作用。PKCα特异性调节pma诱导的脱落，PKCδ和ERK通过明显影响细胞表面HB-EGF的水平来影响组成型和诱导型脱落。总之，这些发现表明存在多种调节模式控制EGFR配体的可用性和随后的EGFR信号转导。
Epidermal growth factor receptor (EGFR) signalling is initiated by the release of EGFR-ligands from membrane-anchored precursors, a process termed ectodomain shedding. This proteolytic event, mainly executed by A Disintegrin And Metalloproteases (ADAMs), is regulated by a number of signal transduction pathways, most notably those involving protein kinase C (PKC). However, the molecular mechanisms of PKC-dependent ectodomain shedding of EGFR-ligands, including the involvement of specific PKC isoforms and possible functional redundancy, are poorly understood. To address this issue, we employed a cell-based system of PMA-induced PKC activation coupled with shedding of heparin binding (HB)-EGF. In agreement with previous studies, we demonstrated that PMA triggers a rapid ADAM17-mediated release of HB-EGF. However, PMA-treatment also results in a protease-independent loss of cell surface HB-EGF. We identified PKCα as the key participant in the activation of ADAM17 and suggest that it acts in parallel with a pathway linking PKCδ and ERK activity. While PKCα specifically regulated PMA-induced shedding, PKCδ and ERK influenced both constitutive and inducible shedding by apparently affecting the level of HB-EGF on the cell surface. Together, these findings indicate the existence of multiple modes of regulation controlling EGFR-ligand availability and subsequent EGFR signal transduction.
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