In multicellular systems, cell division is a key process for morphogenesis and tissue homeostasis. The mitotic spindle plays a fundamental role in epithelial divisions of stem cells and somatic cells as it determines the division axis. Consistently, deregulation of orientation mechanisms leads to tissue disorganization and tumor-like proliferation. The most conserved spindle orientation pathway relies on Galphai/LGN/NuMA complexes that localize at the cell cortex and generate pulling forces on astral microtubules (MTs) via direct interaction of NuMA with the dynein/dynactin MT-motors. External cues also seem fundamental in mitotic spindle positioning. Specifically, the constitutive membrane protein of caveolae, Caveolin1, has been implicated in instructing the distribution of Galphai/LGN/NuMA cortical force generators based on interphase adhesion geometry. Caveolin1 interacts and co-localizes with Gαi1 on the plasma membrane at the proximal end of the retraction fibres and its depletion randomizes the orientation. Proteomic studies indicated that in mitosis Caveolin-1 interacts with NuMA. In addition, we have biochemical evidence for the interaction of Caveolin1 with the cortical actin-binding protein Afadin and with the adherens-junction protein -catenin. I will present biochemical approaches developed to reconstitute from recombinant sources the interaction of Caveolin-1 with spindle orientation proteins and junctional components with the goal of obtaining high-resolution structural information to clarify the role of Caveolin1 in mitosis.

Structural basis of Caveolin1-mediated oriented cell division

Francesca Rizzelli;
2019

Abstract

In multicellular systems, cell division is a key process for morphogenesis and tissue homeostasis. The mitotic spindle plays a fundamental role in epithelial divisions of stem cells and somatic cells as it determines the division axis. Consistently, deregulation of orientation mechanisms leads to tissue disorganization and tumor-like proliferation. The most conserved spindle orientation pathway relies on Galphai/LGN/NuMA complexes that localize at the cell cortex and generate pulling forces on astral microtubules (MTs) via direct interaction of NuMA with the dynein/dynactin MT-motors. External cues also seem fundamental in mitotic spindle positioning. Specifically, the constitutive membrane protein of caveolae, Caveolin1, has been implicated in instructing the distribution of Galphai/LGN/NuMA cortical force generators based on interphase adhesion geometry. Caveolin1 interacts and co-localizes with Gαi1 on the plasma membrane at the proximal end of the retraction fibres and its depletion randomizes the orientation. Proteomic studies indicated that in mitosis Caveolin-1 interacts with NuMA. In addition, we have biochemical evidence for the interaction of Caveolin1 with the cortical actin-binding protein Afadin and with the adherens-junction protein -catenin. I will present biochemical approaches developed to reconstitute from recombinant sources the interaction of Caveolin-1 with spindle orientation proteins and junctional components with the goal of obtaining high-resolution structural information to clarify the role of Caveolin1 in mitosis.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12076/6397
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