Phosphorylation of Kibra by RSK regulates binding to Cdk4 to control cell cycle progression and organ growth independently of the Hippo-pathway

Abstract

Abstract The conserved adapter protein KIBRA (Kidney and Brain) has been described as an upstream regulator of the Hippo signaling cascade, which controls cell proliferation, apoptosis, differentiation and organ growth. Components of this pathway, including KIBRA, are often downregulated or mutated in various types of cancer. KIBRA is phosphorylated at a conserved threonine residue by Ribosomal S6 kinase (RSK), but the function of this phosphorylation in vivo is still unclear. In this study we show that overexpression of Kibra in Drosophila eyes and wings decreases organ growth and that this effect is strongly enhanced upon mutation of the RSK-phosphorylation site in Kibra. Notably, the reduced cell proliferation that leads to impaired organ growth does not depend on the activity of Yorkie as the downstream effector of the Hippo signaling cascade. Instead, Kibra phosphorylation by RSK enables binding to 14-3-3 proteins, which displace Cyclin-dependent kinase 4 (Cdk4) from Kibra, resulting in cell cycle progression. Consequently, overexpression or knockin of a non-phosphorylatable Kibra variant blocks release of Cdk4 from Kibra, retaining cells in G1 phase, which leads to a decreased cell proliferation and thus inhibition of organ and organism growth. Our results elucidate a novel, Hippo pathway-independent function of Kibra in cell cycle regulation and control of organ growth.