Department of Cell Engineering, Beijing Institute of Biotechnology, Bejing 100850, China.
Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, China.
Sci Adv. 2023 Jun 9;9(23):eade1155. doi: 10.1126/sciadv.ade1155.
The EGFR-RAS-ERK pathway plays a key role in cancer development and progression. However, the integral assembly of EGFR-RAS-ERK signaling complexes from the upstream component EGFR to the downstream component ERK is largely unknown. Here, we show that hematopoietic PBX-interacting protein (HPIP) interacts with all classical components of the EGFR-RAS-ERK pathway and forms at least two complexes with overlapping components. Experiments of HPIP knockout or knockdown and chemical inhibition of HPIP expression showed that HPIP is required for EGFR-RAS-ERK signaling complex formation, EGFR-RAS-ERK signaling activation, and EGFR-RAS-ERK signaling-mediated promotion of aerobic glycolysis as well as cancer cell growth in vitro and in vivo. HPIP expression is correlated with EGFR-RAS-ERK signaling activation and predicts worse clinical outcomes in patients with lung cancer. These results provide insights into EGFR-RAS-ERK signaling complex formation and EGFR-RAS-ERK signaling regulation and suggest that HPIP may be a promising therapeutic target for cancer with dysregulated EGFR-RAS-ERK signaling.
EGFR-RAS-ERK 通路在癌症的发生和发展中起着关键作用。然而，EGFR 上游组分到 ERK 下游组分的 EGFR-RAS-ERK 信号复合物的整体组装在很大程度上是未知的。在这里，我们表明造血 PBX 相互作用蛋白 (HPIP) 与 EGFR-RAS-ERK 通路的所有经典成分相互作用，并与重叠成分形成至少两个复合物。HPIP 敲除或敲低实验以及 HPIP 表达的化学抑制实验表明，HPIP 是 EGFR-RAS-ERK 信号复合物形成、EGFR-RAS-ERK 信号激活以及 EGFR-RAS-ERK 信号介导的促进有氧糖酵解所必需的，并且在体外和体内促进癌细胞生长。HPIP 表达与 EGFR-RAS-ERK 信号激活相关，并预测肺癌患者的临床预后更差。这些结果为 EGFR-RAS-ERK 信号复合物的形成和 EGFR-RAS-ERK 信号的调节提供了深入的了解，并表明 HPIP 可能是一种有前途的治疗靶点，用于治疗 EGFR-RAS-ERK 信号失调的癌症。
