Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson’s
disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for
age-related neurodegeneration. Although the cellular functions of LRRK2 in health and
disease are incompletely understood, robust evidence indicates that PD-associated
mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of
the downstream signaling pathways. We have previously demonstrated that one LRRK2
binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the
PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase
dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and
this phosphorylation serves as a switch to dissociate the chaperone from client proteins
including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ
phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935,
causing LRRK2 dephosphorylation. To address whether these interactions are relevant in
a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the
G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our
results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism
of 14-3-3/LRRK2 complex in the brain