Figure 8. Model of LRRK2 regulation of AP2M1 phosphorylation cycles to mediate endocytosis.

Endogenous LRRK2 phosphorylates AP2M1 at Thr¹⁵⁶ at plasma membrane, increases AP2M1 membrane association and, in turn, promotes the initiation of CCV formation (“1”). Knockout of LRRK2 inhibits this initial step. After CCV formation and subsequent scission (“2”), AP2M1 dephosphorylation promotes its uncoating from CCVs, a critical process required for the new cycle of CCV formation (“3”). However, overexpression of LRRK2 or excessive LRRK2 kinase activity such as LRRK2 GS mutant inhibits AP2M1 dephosphorylation after CCV scission and results in inhibition of AP2M1 uncoating for the new cycle of CCV formation.