SHIP2 Regulates Lumen Generation, Cell Division, and Ciliogenesis through the Control of Basolateral to Apical Lumen Localization of Aurora A and HEF 1

Abstract

Lumen formation during epithelial morphogenesis requires the creation of a luminal space at cell interfaces named apical membrane-initiation sites (AMISs). This is dependent upon integrated signaling from mechanical and biochemical cues, vesicle trafficking, cell division, and processes tightly coupled to ciliogenesis. Deciphering relationships between polarity determinants and lumen or cilia generation remains a fundamental issue. Here, we report that Src homology 2 domain-containing inositol 5-phosphatase 2 (SHIP2), a basolateral determinant of polarity, regulates RhoA-dependent actin contractility and cell division to form AMISs. SHIP2 regulates mitotic spindle alignment. SHIP2 is expressed in G1 phase, whereas Aurora A kinase is enriched in mitosis. SHIP2 binds Aurora A kinase and the scaffolding protein HEF1 and promotes their basolateral localization at the expense of their luminal expression connected with cilia resorption. Furthermore, SHIP2 expression increases cilia length. Thus, our findings offer new insight into the relationships among basolateral proteins, lumen generation, and ciliogenesis.

Insane in the apical membrane: Trafficking events mediating apicobasal epithelial polarity during tube morphogenesis

“…Thus, it is conceivable that if the cells divide in the wrong plane, either due to misalignment of the microtubule spindle or cleavage furrow ingression direction, erroneous lumens may arise from each cell division. There are a number of proteins known to regulate spindle orientation during lumen expansion, including Cdc42 and its GEFs and GAPs 54–57 , polarity complex proteins 55,58 , phosphatidylinositol phosphatases 59 , microtubule binding proteins 60 , and other small GTPases 61 . Consequently, while apical membrane biogenesis is crucial for lumen formation, proper orientation of later cytokinesis events is also essential for expansion and maintenance of a single lumen.…”

RACK1 affects the progress of G2/M by regulating Aurora-A

“…In addition to RACK1, there are many other proteins lacking enzymatic activity, such as cofactors Tpx2 [29], HEF1 [30], Ajuba [6,8], FAK [31,32], and Bora [33] or even protein phosphatases, may also regulate the initial activation of Aurora-A. Our study adds RACK1 to the list of physiological upstream activators of Aurora-A.…”

The regulation of cilium assembly and disassembly in development and disease

“…Aurora A activity is also regulated by phosphoinositide signaling. Cultured cells grown in three dimensions develop a lumen with cilia and, in this context, the phosphatidylinositol phosphatase SHIP2 was found to bind Aurora A and NEDD9, and to promote their basolateral localization at the expense of their luminal expression associated with cilium resorption (Hamze-Komaiha et al, 2016). Moreover, INPP5E regulates Aurora A protein levels through transcriptional mechanisms that are mediated, at least in part, by AKT activity (Plotnikova et al, 2015).…”