α4 Is an Essential Regulator of PP2A Phosphatase Activity

The activity and specificity of serine/threonine phosphatases are governed largely by their associated proteins. alpha 4 is an evolutionarily conserved noncatalytic subunit for PP2A-like phosphatases. Though alpha 4 binds to only a minority of PP2A-related catalytic subunits, alpha 4 deletion leads to progressive loss of all PP2A, PP4, and PP6 phosphatase complexes. In healthy cells, association with alpha 4 renders catalytic (C) subunits enzymatically inactive while protecting them from proteasomal degradation until they are assembled into a functional phosphatase complex. During cellular stress, existing PP2A complexes can become unstable. Under such conditions, alpha 4 sequesters released C subunits and is required for the adaptive increase in targeted PP2A activity that can dephosphorylate stress-induced phosphorylated substrates. Consistent with this, overexpression of alpha 4 protects cells from a variety of stress stimuli, including DNA damage and nutrient limitation. These findings demonstrate that alpha 4 plays a required role in regulating the assembly and maintenance of adaptive PP2A phosphatase complexes.