AMBRA1 phosphorylation by CDK1 and PLK1 regulates mitotic spindle orientation

AMBRA1 is a crucial factor for nervous system development, and its\r\nfunction has been mainly associated with autophagy. It has been also\r\nlinked to cell proliferation control, through its ability to regulate\r\nc-Myc and D-type cyclins protein levels, thus regulating G1-S\r\ntransition. However, it remains still unknown whether AMBRA1 is\r\ndifferentially regulated during the cell cycle, and if this\r\npro-autophagy protein exerts a direct role in controlling mitosis too.\r\nHere we show that AMBRA1 is phosphorylated during mitosis on multiple\r\nsites by CDK1 and PLK1, two mitotic kinases. Moreover, we demonstrate\r\nthat AMBRA1 phosphorylation at mitosis is required for a proper spindle\r\nfunction and orientation, driven by NUMA1 protein. Indeed, we show that\r\nthe localization and/or dynamics of NUMA1 are strictly dependent on\r\nAMBRA1 presence, phosphorylation and binding ability. Since spindle\r\norientation is critical for tissue morphogenesis and differentiation,\r\nour findings could account for an additional role of AMBRA1 in\r\ndevelopment and cancer ontogenesis.