ACKnowledging the role of the Activated-Cdc42 associated kinase (ACK) in regulating protein stability in cancer.
ACKnowledging the role of the Activated-Cdc42 associated kinase (ACK) in regulating protein stability in cancer.
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DOI：
10.1080/21541248.2023.2212573
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发表时间：
2023-12
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活化的CDC42相关激酶(ACK)是一种非受体酪氨酸激酶，是小分子GTP酶CDC42的效应器。ACK正在成为癌症版图的一个重要组成部分，因此，它是许多恶性肿瘤治疗的一个有前途的靶点。ACK也被越来越多地认为是调节蛋白质稳态的一个潜在的有影响力的参与者。蛋白质合成和蛋白质降解之间的微妙平衡对健康的细胞功能至关重要，蛋白质稳态失调是人类疾病中常见的现象。在这里，我们回顾了ACK调节不同细胞蛋白(如EGFR、p27、P53、P85亚型和RhoGDI-3)稳定性的分子机制，其中一些依赖于ACK的激酶活性，而另一些则不依赖。最终，将需要进一步的研究来弥合我们的知识差距，并确定ACK是否调节更多细胞蛋白质的稳定性，但总的来说，这种机械性的询问将有助于确定ACK是否是抗癌治疗的有希望的靶点。在治疗学中，蛋白酶体抑制剂是一类有效但有问题的药物。以ACK等其他蛋白平衡调节剂为靶点，可能会为干预开辟新的途径。
Activated Cdc42-associated kinase (ACK), a non-receptor tyrosine kinase, is an effector for the small GTPase Cdc42. ACK is emerging as an important component of the cancer landscape and thus, a promising target for the treatment of many malignancies. ACK is also being increasingly recognized as a potentially influential player in the regulation of protein homoeostasis. The delicate equilibrium between protein synthesis and protein degradation is crucial for healthy cell function and dysregulation of protein homoeostasis is a common occurrence in human disease. Here, we review the molecular mechanisms by which ACK regulates the stability of diverse cellular proteins (e.g. EGFR, p27, p53, p85 isoforms and RhoGDI-3), some of which rely on the kinase activity of ACK while others, interestingly, do not. Ultimately, further research will be required to bridge our knowledge gaps and determine if ACK regulates the stability of further cellular proteins but collectively, such mechanistic interrogation would contribute to determining whether ACK is a promising target for anti-cancer therapy. In therapeutics, proteasome inhibitors are an efficacious but problematic class of drugs. Targeting other modulators of proteostasis, like ACK, could open novel avenues for intervention.