LRRK2 directly phosphorylates Akt1 as a possible physiological substrate: Impairment of the kinase activity by Parkinson’s disease-associated mutations

• Published in: FEBS letters Vol. 585; no. 14; pp. 2165 - 2170
• Main Authors: Ohta, Etsuro, Kawakami, Fumitaka, Kubo, Makoto, Obata, Fumiya
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 21.07.2011
• Subjects: Akt1; Animals; Cell Line; Gene Knockdown Techniques; Humans; Leucine-rich repeat kinase 2; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; PARK8; Parkinson Disease - genetics; Parkinson Disease - physiopathology; Parkinson's disease; Phosphorylation; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Signal Transduction - physiology; Akt1; PARK8; Leucine-rich repeat kinase 2; Parkinson’s disease
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2011.05.044

► We found that LRRK2 directly phosphorylated Akt1 at Ser473. ► The knockdown of LRRK2 resulted in a marked reduction of phospho-Akt1 at Ser473. ► The R1441C, G2019S, and I2020T mutant LRRK2 exhibited reduced interaction with, and phosphorylation of, Akt1. ► Akt1 is one of the physiological substrates of LRRK2. LRRK2 is the causal molecule for autosomal-dominant familial Parkinson’s disease, although its true function, including its physiological substrates, remains unknown. Here, using in vitro kinase assay with recombinant proteins, we demonstrated for the first time that LRRK2 directly phosphorylates Akt1, a central molecule involved in signal transduction for cell survival and prevention of apoptosis. Ser473, one of two amino acids essential for Akt1 activation, was the target site for LRRK2. A knockdown experiment using intact cells also demonstrated LRRK2-mediated phosphorylation of Akt1 (Ser473), suggesting that Akt1 is a convincing candidate for the physiological substrate of LRRK2. The disease-associated mutations, R1441C, G2019S, and I2020T, exhibited reduced interaction with, and phosphorylation of, Akt1, suggesting one possible mechanism for the neurodegeneration caused by LRRK2 mutations. LRRK2phosphorylatesAkt1 by protein kinase assay (View Interaction 1, 2, 3). LRRK2phosphorylatesMBP by protein kinase assay (View Interaction 1, 2). LRRK2binds to Akt1 by pull down (View Interaction 1, 2, 3).