Akt Regulates a Rab11-Effector Switch Required for Ciliogenesis

  • Dev Cell. 2019 Jul 22;50(2):229-246.e7. doi: 10.1016/j.devcel.2019.05.022.
Vijay Walia  1 ,  Adrian Cuenca  1 ,  Melanie Vetter  2 ,  Christine Insinna  1 ,  Sumeth Perera  1 ,  Quanlong Lu  1 ,  Daniel A Ritt  1 ,  Elizabeth Semler  1 ,  Suzanne Specht  1 ,  Jimmy Stauffer  1 ,  Deborah K Morrison  1 ,  Esben Lorentzen  2 ,  Christopher J Westlake  3
Affiliations
  • 1. Center for Cancer Research, NCI Frederick, Laboratory of Cellular and Developmental Signaling, Frederick, MD 21702, USA.
  • 2. Department of Molecular Biology and Genetics, Aarhus University, Gustav Wieds Vej 10c, 8000 Aarhus C, Denmark.
  • 3. Center for Cancer Research, NCI Frederick, Laboratory of Cellular and Developmental Signaling, Frederick, MD 21702, USA. Electronic address: [email protected].
PMID: 31204173 DOI: 10.1016/j.devcel.2019.05.022
Abstract

Serum starvation stimulates cilia growth in cultured cells, yet serum factors associated with ciliogenesis are unknown. Previously, we showed that starvation induces rapid Rab11-dependent vesicular trafficking of Rabin8, a Rab8 guanine-nucleotide exchange factor (GEF), to the mother centriole, leading to Rab8 activation and cilium growth. Here, we demonstrate that through the LPA receptor 1 (LPAR1), serum lysophosphatidic acid (LPA) inhibits Rab11a-Rabin8 interaction and ciliogenesis. LPA/LPAR1 regulates ciliogenesis initiation via downstream PI3K/Akt activation, independent of effects on cell cycle. Akt stabilizes Rab11a binding to its effector, WDR44, and a WDR44-pAkt-phosphomimetic mutant blocks ciliogenesis. WDR44 depletion promotes Rabin8 preciliary trafficking and ciliogenesis-initiating events at the mother centriole. Our work suggests disruption of Akt signaling causes a switch from Rab11-WDR44 to the ciliogenic Rab11-FIP3-Rabin8 complex. Finally, we demonstrate that Akt regulates downstream ciliogenesis processes associated with Rab8-dependent cilia growth. Together, this study uncovers a mechanism whereby serum mitogen signaling regulates Rabin8 preciliary trafficking and ciliogenesis initiation.

Keywords
Akt; FIP3; LPA; MC; Rab11 effector switch; Rabin8; WDR44; ciliogenesis; lysophosphatidic acid; mother centriole; phosphorylation; preciliary trafficking.