Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling.
Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling.
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DOI：
10.1016/j.molcel.2016.04.003
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发表时间：
2016-05-05
期刊：
影响因子：
16
通讯作者：
Witze ES
中科院分区：
文献类型：
--
作者：
Runkle KB;Kharbanda A;Stypulkowski E;Cao XJ;Wang W;Garcia BA;Witze ES
受体酪氨酸激酶EGFR的不适当活化导致多种人类恶性肿瘤。在这里，我们展示了诱导对EGFR驱动的癌症的现有一线治疗的易感性的机制。我们发现，抑制棕榈酰转移酶DHHC 20产生了对EGFR信号传导的依赖，从而使癌细胞存活。棕榈酰化的丧失增加了持续的EGFR信号激活，并使细胞对EGFR酪氨酸激酶抑制敏感。我们的工作表明，用棕榈酸酯对EGFR的可逆修饰将非结构化的C-末端尾“钉”在质膜上;阻碍EGFR活化。我们通过质谱鉴定了C-末端尾部内的棕榈酰化半胱氨酸残基，其中半胱氨酸残基突变为丙氨酸足以激活EGFR信号传导，促进细胞迁移和转化。我们的研究结果表明，靶向EGFR信号传导的外周调节剂DHHC 20，导致信号调节的丧失和对EGFR抑制剂诱导的细胞死亡的易感性。
Inappropriate activation of the receptor tyrosine kinase EGFR contributes to a variety of human malignancies. Here we show a mechanism to induce vulnerability to an existing first line treatment for EGFR driven cancers. We find that inhibiting the palmitoyltransferase DHHC20 creates a dependence on EGFR signaling for cancer cell survival. The loss of palmitoylation increases sustained EGFR signal activation and sensitizes cells to EGFR tyrosine kinase inhibition. Our work shows that the reversible modification of EGFR with palmitate “pins” the unstructured C-terminal tail to the plasma membrane; impeding EGFR activation. We identify by mass spectrometry palmitoylated cysteine residues within the C-terminal tail where mutation of the cysteine residues to alanine is sufficient to activate EGFR signaling promoting cell migration and transformation. Our results reveal that the targeting of a peripheral modulator of EGFR signaling, DHHC20, causes a loss of signal regulation and susceptibility to EGFR inhibitor induced-cell death.