细胞外 PKCδ 向表皮生长因子受体发出信号以促进肝癌细胞的肿瘤增殖,Cancer Science

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细胞外 PKCδ 向表皮生长因子受体发出信号以促进肝癌细胞的肿瘤增殖
Cancer Science ( IF 4.5 ) Pub Date : 2022-05-01 , DOI: 10.1111/cas.15386
Kohji Yamada ₁ , Ryusuke Kizawa ₁ , Ayano Yoshida ₁ , Rei Koizumi ₁ , Saya Motohashi ₁ , Yuya Shimoyama ₁ , Yoshito Hannya ₁ , Saishu Yoshida ₁ , Tsunekazu Oikawa ₂ , Masayuki Shimoda ₃ , Kiyotsugu Yoshida ₁

Affiliation

蛋白激酶 C δ (PKCδ) 是多功能 PKC 家族成员，与多种癌症有关，包括肝癌。最近，我们报道了PKCδ由肝癌细胞分泌，参与细胞增殖和肿瘤生长。然而，尚不清楚细胞外PKCδ是否直接调节细胞表面生长因子受体。在这里，我们将表皮生长因子受体 (EGFR) 鉴定为肝癌细胞中细胞表面 PKCδ 的新型相互作用蛋白。影像学研究表明，分泌的 PKCδ 以自分泌和旁分泌方式与 EGFR 表达细胞相互作用。生化分析显示PKCδ与EGFR的细胞外结构域结合。我们进一步发现PKCδC端区域的部分氨基酸序列与EGF推定的EGFR结合位点相似。在这方面，PKCδ在结合位点的点突变体缺乏结合EGFR胞外结构域的能力。在细胞外 PKCδ-EGFR 结合后，在肝癌细胞中明显诱导了 EGFR 信号下游的 ERK1/2 活化。该研究表明，细胞外 PKCδ 作为一种生长因子发挥作用，并为肝癌细胞外 PKCδ 靶向治疗提供了分子基础。

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Extracellular PKCδ signals to epidermal growth factor receptor for tumor proliferation in liver cancer cells

Protein kinase C delta (PKCδ) is a multifunctional PKC family member and has been implicated in many types of cancers, including liver cancer. Recently, we have reported that PKCδ is secreted from liver cancer cells, and involved in cell proliferation and tumor growth. However, it remains unclear whether the extracellular PKCδ directly regulates cell surface growth factor receptors. Here, we identify epidermal growth factor receptor (EGFR) as a novel interacting protein of the cell surface PKCδ in liver cancer cells. Imaging studies showed that secreted PKCδ interacted with EGFR-expressing cells in both autocrine and paracrine manners. Biochemical analysis revealed that PKCδ bound to the extracellular domain of EGFR. We further found that a part of the amino acid sequence on the C-terminal region of PKCδ was similar to the putative EGFR binding site of EGF. In this regard, the point mutant of PKCδ in the binding site lacked the ability to bind to the extracellular domain of EGFR. Upon an extracellular PKCδ-EGFR association, ERK1/2 activation, downstream of EGFR signaling, was apparently induced in liver cancer cells. This study indicates that extracellular PKCδ behaves as a growth factor and provides a molecular basis for extracellular PKCδ-targeting therapy for liver cancer.

更新日期：2022-05-01

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