Proposed mechanism for regulation of actin assembly by CapZ acting as a destination to integrate several signaling pathways by phosphorylation, acetylation, and PIP2 binding. (A) CapZ caps the actin of the thin filament in the Z disc, shown in a stable sarcomere (left) or one undergoing hypertrophy (right). (B) Based on studies from many groups (Kim et al., 2007; Kuhn and Pollard, 2007; Smith et al., 2006) and the FRET and FRAP data in this paper, CapZ is shown at the molecular scale as bound to actin tightly in the locked/idle state, with little phosphorylation or PIP2 binding. However, this tight binding is loosened in growth states of hypertrophy triggered by stimuli such as mechanical flexing, loading, stiffer substrate, angiotensin II, and phenylephrine. Signaling pathways from these stimuli modify CapZ at the actin binding face by PKC phosphorylation (S204), acetylation (K199), or PIP2 binding. Additionally, PIP2 and T267 phosphorylation interact near the β-tentacle to modulate CapZ dynamics. Growth only occurs when the CapZ is in the unlocked/dynamic state by a combination of several signaling pathways at both the actin binding face and the β-tentacle.