Clathrin-Independent Endocytosis Suppresses Cancer Cell Blebbing and Invasion

Publication date: 22 August 2017
Source:Cell Reports, Volume 20, Issue 8
Author(s): Mikkel Roland Holst, Maite Vidal-Quadras, Elin Larsson, Jie Song, Madlen Hubert, Jeanette Blomberg, Magnus Lundborg, Maréne Landström, Richard Lundmark
Cellular blebbing, caused by local alterations in cell-surface tension, has been shown to increase the invasiveness of cancer cells. However, the regulatory mechanisms balancing cell-surface dynamics and bleb formation remain elusive. Here, we show that an acute reduction in cell volume activates clathrin-independent endocytosis. Hence, a decrease in surface tension is buffered by the internalization of the plasma membrane (PM) lipid bilayer. Membrane invagination and endocytosis are driven by the tension-mediated recruitment of the membrane sculpting and GTPase-activating protein GRAF1 (GTPase regulator associated with focal adhesion kinase-1) to the PM. Disruption of this regulation by depleting cells of GRAF1 or mutating key phosphatidylinositol-interacting amino acids in the protein results in increased cellular blebbing and promotes the 3D motility of cancer cells. Our data support a role for clathrin-independent endocytic machinery in balancing membrane tension, which clarifies the previously reported role of GRAF1 as a tumor suppressor.

Graphical abstract

Teaser

Holst et al. show that clathrin-independent endocytosis facilitates the rearrangement of the cell surface in response to a decrease in cell volume. This regulation, mediated by the protein GRAF1, suppresses cellular blebbing and the invasiveness of cancer cells, clarifying why GRAF1 acts as a tumor suppressor.


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