APH1A encodes a non-catalytic subunit essential for gamma-secretase complex assembly and function. The gamma-secretase complex is an endoprotease that catalyzes intramembrane cleavage of integral membrane proteins, including Notch receptors and amyloid precursor protein (APP) 1. APH1A is required for normal gamma-secretase assembly, with the complex consisting of presenilin, nicastrin, PEN-2, and APH1A subunits 1. The protein undergoes regulatory phosphorylation by GPCR kinases, which generates distinct phosphorylation patterns that differentially regulate β-arrestin 2 recruitment and amyloid-β generation 2. APH1A serves as a direct target of microRNA-138, which acts as a tumor suppressor by inhibiting the NOTCH1 pathway in renal cell carcinoma 3. The gamma-secretase complex containing APH1A plays crucial roles in Notch and Wnt signaling cascades, with selective inhibition of specific gamma-secretase subcomplexes being explored as therapeutic targets 4. Recent studies suggest APH1A may represent a druggable target for chr1 obstructive pulmonary disease treatment 5. Under physiological conditions, endogenous APH1A does not undergo proteasomal degradation, though overexpressed forms may be artifactually degraded 6.