Department of Medical Sciences, Dermatology and Venereology, University Hospital, Uppsala University, SE-751 85 Uppsala, Sweden.
J Dermatol Sci. 2010 Jul;59(1):7-15. doi: 10.1016/j.jdermsci.2010.03.017. Epub 2010 Apr 3.
Ligand-stimulated epidermal growth factor receptor (EGFR/HER1) plays a fundamental role in skin biology as potent transducer of mitotic and anti-apoptotic stimuli in keratinocytes. In human epidermis, at least two additional EGFR family members--HER2 and HER3--are expressed but their biological functions in normal and diseased human skin remain obscure.
Here, we studied the expression and biological impact of HER3 in regenerating human epidermis formed from skin explants adhered to acellular dermis.
Neoepidermal HER3 expression was examined by quantitative real-time reverse transcriptase polymerase chain reaction, immunohistochemistry and Western blot analysis. The dynamic effect of HER3 receptor stimulation by recombinant heregulin (HRG)-beta1 was assessed by fluorescence imaging of re-epithelialization.
In the neoepidermis, HER3 mRNA and protein were detected with activated receptors being immunolocalized at basal and low suprabasal levels. Exogenous HRG-beta1 at 10-20 ng/ml increased the outgrowth rate corresponding to approximately 30% the response of exogenous EGF. The growth-promoting effect of HRG-beta1 was associated with enhanced HER3 phosphorylation, keratinocyte proliferation and thickening of viable neoepidermis whereas blockade of ligand-binding to HER3 delayed the outgrowth process and inhibited both constitutive and ligand-induced HER3 phosphorylation. HER2 antagonism using an anti-dimerization antibody, pertuzumab, impeded the re-epithelialization rate. In addition, a selective HER2 kinase inhibitor, CP654577, downregulated phospho-HER3 expression suggesting that transactivation of kinase-deficient HER3 was accomplished through dimerization with HER2.
The study emphasizes the central role of EGFR in epidermal renewal and demonstrates that HRG-activated HER3 contributes to the outgrowth process of epidermis in vitro.
配体刺激的表皮生长因子受体（EGFR/HER1）在皮肤生物学中起着至关重要的作用，作为角质细胞有丝分裂和抗凋亡刺激的有效转导器。在人类表皮中，至少表达了另外两个 EGFR 家族成员——HER2 和 HER3——但其在正常和患病人类皮肤中的生物学功能尚不清楚。
本研究旨在探讨 HER3 在附着于脱细胞真皮的皮肤外植体形成的再生人表皮中的表达及其生物学影响。
通过定量实时逆转录聚合酶链反应、免疫组织化学和 Western blot 分析检测新表皮中 HER3 的表达。通过荧光成像评估重组人表皮生长因子（HRG）-β1 对 HER3 受体的刺激作用。
在新表皮中，检测到 HER3 mRNA 和蛋白，激活的受体免疫定位在基底和低至上皮水平。10-20ng/ml 的外源性 HRG-β1 可增加表皮再生率，约为外源性 EGF 反应的 30%。HRG-β1 的促生长作用与增强的 HER3 磷酸化、角质形成细胞增殖和存活的新表皮增厚有关，而阻断配体与 HER3 的结合则延迟了表皮再生过程并抑制了 HER3 的组成性和配体诱导磷酸化。使用抗二聚化抗体 pertuzumab 拮抗 HER2 会阻碍表皮再上皮化的速度。此外，选择性 HER2 激酶抑制剂 CP654577 下调了磷酸化 HER3 的表达，表明激酶缺陷的 HER3 通过与 HER2 二聚化来实现转激活。
该研究强调了 EGFR 在表皮更新中的核心作用，并证明 HRG 激活的 HER3 有助于体外表皮的生长过程。
