INPP5E interacts with AURKA, linking phosphoinositide signalling to primary cilium stability

Abstract

Mutations in inositol polyphosphate 5-phosphatase E (INPP5E) cause the ciliopathies known as Joubert and MORM syndromes; however, the role of INPP5E in ciliary biology is not well understood. Here, we describe an interaction between INPP5E and AURKA, a centrosomal kinase that regulates mitosis and ciliary disassembly, and we show that this interaction is important for the stability of primary cilia. Furthermore, AURKA phosphorylates INPP5E and thereby increases its 5-phosphatase activity, which in turn promotes transcriptional downregulation of AURKA, partly through an AKTdependent mechanism. These findings establish the first direct link between AURKA and phosphoinositide signaling and suggest that the function of INPP5E in cilia is at least partly mediated by its interactions with AURKA.

Role of Ocrl1 and Inpp5E in primary cilia assembly and maintenance: a phosphatidylinositol phosphatase relay system?

“…82 Synergistic to this effect, Inpp5E-mediated hydrolysis of PI(3,4,5)P 3 is linked to inhibition of the PI3K/AKT signaling pathway. As expected, Inpp5E-deficient cells displayed high levels of PI(3,4,5)P 3 85 and increased phospho-Akt levels; 83 further, cells expressing Joubert syndrome Inpp5E mutants also show high levels of phosphorylated Akt. 85 Recently, mouse …”

“…37,81 Inpp5E is known to be tyrosine phosphorylated by activated insulin receptor 82 and Ser/Thr-phosphorylated by Aurora kinase A (AurkA). 83 In addition to hydrolyzing the product of PI3K enzymatic activity, it has been reported that Inpp5E interacts with p85 subunit of PI3K, negatively regulating the Akt pathway, and also binds Insulin receptor substrate 2(IRS2). 82,84 A yeast two-hybrid screen identified Rab20, a Golgi-and phagosome-localized protein as the only Rab GTPase that interacts with Inpp5E.…”

“…8,9 Importantly, Plotnikova et al 83 showed that Inpp5E directly interacts with AurkA, resulting in the phosphorylation of Inpp5E by AurkA and the enhancement of its catalytic activity toward PI(3,4,5)P 3 (particularly at the base of the PC where the kinase localizes 88 ). Interestingly, AurkA is one of the targets modulated by the Akt signaling pathway 89 and has been involved in the regulation of PC stability through complex formation with histone deacetylase 6 (HDAC6).…”

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

“…VAV2 is a coactivator of androgen receptor (AR) and sustains AR signaling under androgen deprivation therapy (ADT) (Magani et al ., 2017); it also promotes angiogenesis and metastasis (Barrio‐Real and Kazanietz, 2012). AURKA plays a critical role in mitosis (Dominguez‐Brauer et al ., 2015; Plotnikova et al ., 2015) and promotes the development of neuroendocrine PC under ADT (Beltran et al ., 2011; Mosquera et al ., 2013). DNMT3B may regulate epigenetic events to facilitate CRPC development (Hoffmann et al ., 2007).…”

“…AURKA is emerging as an important regulator of mitosis and a critical player in tumorigenesis. As such, AURKA is a hotly pursued in cancer therapy (Dominguez‐Brauer et al ., 2015; Plotnikova et al ., 2015). Additionally, OIP5 is also known as Mis18β which has recently been shown to play an important role in chromatid separation during mitosis (Nardi et al ., 2016; Stellfox et al ., 2016), adding another appealing feature for its inclusion in SigMuc1NW.…”