| CAB39, also known as MO25, is an armadillo repeat–containing scaffolding protein that forms a core component of the LKB1–STRAD–MO25 complex, which acts as the principal upstream kinase module for AMPK and a family of related kinases that regulate cellular energy sensing, polarity, and stress responses. The protein is built from tandem armadillo repeats that generate a curved surface for high‑affinity interaction with the C‑terminal Trp–Glu–Phe motif of the pseudokinase STRADα, and this binding markedly enhances the association of STRADα with the tumor suppressor kinase LKB1 and stabilizes the heterotrimeric complex. MO25 binding promotes proper folding and cytoplasmic localization of the STRAD–LKB1 complex and increases LKB1 catalytic activity toward downstream substrates, leading to phosphorylation and activation of AMPK and at least a dozen other AMPK‑related kinases that collectively control energy homeostasis, cell polarity, and metabolic adaptation under stress. LKB1–STRAD–MO25 is the major AMPK kinase assembly in tissues such as skeletal muscle, and MO25 acts as an essential cofactor that tunes both the stability and signaling competence of this node rather than contributing catalytic activity itself. CAB39/MO25 is also an important regulatory target for microRNAs that modulate the LKB1–AMPK axis: miR‑451 directly binds a conserved site in the CAB39 3′UTR, reduces CAB39 protein levels, and thereby diminishes LKB1‑dependent AMPK activation, shifting cells toward mTOR signaling and enhanced proliferation and survival in stress conditions. In cardiac and hypertrophic disease models, related microRNAs such as miR‑195 and miR‑451 target CAB39 transcripts and associate with reduced MO25 expression, lowered AMPK phosphorylation, and altered acetyl‑CoA carboxylase phosphorylation, linking CAB39 abundance to metabolic remodeling in the myocardium. |
