Bioscience Division, Oak Ridge National Laboratory, 1 Bethel Valley Rd, Oak Ridge, TN, 37831, USA.
Bredesen Center for Interdisciplinary Research, University of Tennessee, Knoxville, TN, 37996, USA.
Commun Biol. 2022 Jul 1;5(1):646. doi: 10.1038/s42003-022-03582-8.
The Plasminogen-Apple-Nematode (PAN) domain, with a core of four to six cysteine residues, is found in > 28,000 proteins across 959 genera. Still, its role in protein function is not fully understood. The PAN domain was initially characterized in numerous proteins, including HGF. Dysregulation of HGF-mediated signaling results in multiple deadly cancers. The binding of HGF to its cell surface receptor, c-MET, triggers all biological impacts. Here, we show that mutating four core cysteine residues in the HGF PAN domain reduces c-MET interaction, subsequent c-MET autophosphorylation, and phosphorylation of its downstream targets, perinuclear localization, cellular internalization of HGF, and its receptor, c-MET, and c-MET ubiquitination. Furthermore, transcriptional activation of HGF/c-MET signaling-related genes involved in cancer progression, invasion, metastasis, and cell survival were impaired. Thus, targeting the PAN domain of HGF may represent a mechanism for selectively regulating the binding and activation of the c-MET pathway.
纤溶酶原-苹果-线虫 (PAN) 结构域，包含 4 到 6 个半胱氨酸残基核心，存在于超过 959 个属的 28000 多种蛋白质中。尽管如此，其在蛋白质功能中的作用仍未完全阐明。PAN 结构域最初在许多蛋白质中被描述，包括 HGF。HGF 介导的信号转导失调会导致多种致命癌症。HGF 与其细胞表面受体 c-MET 的结合触发了所有的生物学影响。在这里，我们表明，突变 HGF PAN 结构域中的四个核心半胱氨酸残基会降低 c-MET 相互作用、随后的 c-MET 自身磷酸化以及其下游靶标磷酸化、核周定位、HGF 和其受体 c-MET 的细胞内化以及 c-MET 泛素化。此外，还会损害与癌症进展、侵袭、转移和细胞存活相关的 HGF/c-MET 信号转导相关基因的转录激活。因此，靶向 HGF 的 PAN 结构域可能代表一种选择性调节 c-MET 途径结合和激活的机制。
