ACKnowledging the role of the Activated-Cdc42 associated kinase (ACK) in regulating protein stability in cancer

ABSTRACT

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.

KEYWORDS:

• Kinase
• cancer
• proteostasis
• small gtpase

Acknowledgments

This research was supported by an MRes + PhD studentship from the Cancer Research UK Cambridge Centre [CTRQQR-2021\100012] to SH; a studentship to AMbAM from the Ministry of Higher Education, Malaysia and an MRC iCASE (MR/N018354/1) to DO partnered by AstraZeneca.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

The work was supported by the Medical Research Council [MR/N018354/1]; Ministry of Higher Education, Malaysia [Studentship]; Cancer Research UK Cambridge Centre [CTRQQR-2021\100012].