Mooz Juliane, Riegel Kristina, Ps Hari, Sadanandam Anguraj, Marini Federico, Klein Matthias, Werner Ulrike, Roth Wilfried, Wilken-Schmitz Annett, Tegeder Irmgard, Rajalingam Krishnaraj
Cell Biology Unit, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.
Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
Sci Adv. 2022 Mar 18;8(11):eabk1538. doi: 10.1126/sciadv.abk1538.
RAF kinases are highly conserved serine/threonine kinases, and among the three RAF isoforms (ARAF, BRAF, and CRAF), the pathophysiological relevance of ARAF is not well defined. Here, we show that patients with lung cancer exhibit low expression of ARAF, which is associated with lymph node metastasis and poor patient survival. We uncover that depletion of ARAF promotes anchorage-independent growth and metastasis through activation of AKT signaling in a subset of lung cancer cells. We identified that loss of ARAF was associated with an increase in ERBB3 expression in a kinase-independent manner. ARAF suppressed the promoter activity of ERBB3, and reconstitution of ARAF in ARAF-depleted cells led to the reversal of enhanced ERBB3-AKT signaling. Furthermore, ARAF inhibited neuregulin 1 (hNRG1)-mediated AKT activation through controlling ERBB3 expression via the transcription factor KLF5. Our results disclose a critical dual role for ARAF kinase in the negative regulation of ERBB3-AKT signaling, thereby suppressing tumor metastasis.
RAF激酶是高度保守的丝氨酸/苏氨酸激酶，在三种RAF亚型（ARAF、BRAF和CRAF）中，ARAF的病理生理相关性尚未明确界定。在此，我们表明肺癌患者表现出ARAF低表达，这与淋巴结转移和患者预后不良相关。我们发现，在一部分肺癌细胞中，ARAF缺失通过激活AKT信号促进不依赖贴壁的生长和转移。我们确定，ARAF缺失与ERBB3表达以激酶非依赖方式增加有关。ARAF抑制ERBB3的启动子活性，在ARAF缺失的细胞中重新表达ARAF导致增强的ERBB3-AKT信号逆转。此外，ARAF通过转录因子KLF5控制ERBB3表达，抑制神经调节蛋白1（hNRG1）介导的AKT激活。我们的结果揭示了ARAF激酶在负向调节ERBB3-AKT信号从而抑制肿瘤转移中的关键双重作用。
