Going vertical: Functional role and working principles of the protein Inscuteable in asymmetric cell divisions

Coordinating mitotic spindle dynamics with cortical polarity is essential for stem cell asymmetric divisions. Over the years, the protein Inscuteable (Insc) has emerged as a key element determining the spindle orientation in asymmetric mitoses. Its overexpression increases differentiative divisions in systems as diverse as mouse keratinocytes and radial glial cells. To date, the molecular explanation to account for this phenotype envisioned Insc as an adaptor molecule bridging between the polarity proteins Par3:Par6:aPKC and the spindle pulling machines assembled on NuMA:LGN:Gαi. However, recent biochemical and structural data revealed that Insc and NuMA are competitive interactors of LGN, challenging the simplistic idea of a single apical macromolecular complex, and demanding a revision of the actual working principles of Insc.