Cyclin-dependent kinase–activating kinase (CAK)

Cyclin-dependent kinase–activating kinase (CAK) is a multi-subunit serine/threonine protein kinase responsible for the activating phosphorylation of cyclin-dependent kinases such as CDK1, CDK2, CDK4, and CDK6. This phosphorylation occurs on a threonine residue within the activation loop (T-loop) of these kinases and is required for their full enzymatic activity[3][4][5]. In mammals, the canonical CAK consists of three subunits: CDK7 (the catalytic subunit), cyclin H (regulatory subunit), and MAT1 (assembly factor)[4][5]. Beyond its central role in cell cycle control by activating multiple key CDKs, CAK is also an integral component of the general transcription factor TFIIH. Within this context, it regulates promoter clearance and progression during RNA polymerase II-mediated transcription initiation[3][4]. Because it sits at a critical regulatory node for both proliferation and gene expression, dysregulation or inhibition of CAK—particularly via targeting its catalytic subunit CDK7—has been explored as a therapeutic strategy in cancer. However, its ubiquitous function raises concerns about potential toxicity with systemic inhibition[4].

Other names

CDK-activating kinaseCdk7-cyclin H-MAT1 complex (for the human form)CAK complex

Inhibition of CAK prevents activating phosphorylation of CDKs, leading to cell cycle arrest and reduced transcriptional activity[4].