Vesicle trafficking has emerged as an important process driving tumor progression through various mechanisms. Transforming growth factor beta (TGFβ)‐mediated secretion of Angiopoietin‐like 4 (ANGPTL4) is important for cancer development. Here, Formin‐like 2 (FMNL2) is identified to be necessary for ANGPTL4 trafficking and secretion in response to TGFβ. Protein kinase C (PKC)‐dependent phosphorylation of FMNL2 downstream of TGFβ stimulation is required for cancer cell invasion as well as ANGPTL4 vesicle trafficking and secretion. Moreover, using super resolution microscopy, ANGPTL4 trafficking is actin‐dependent with FMNL2 directly polymerizing actin at ANGPTL4‐containing vesicles, which are associated with Rab8a and myosin Vb. This work uncovers a formin‐controlled mechanism that transiently polymerizes actin directly at intracellular vesicles to facilitate their mobility. This mechanism may be important for the regulation of cancer cell metastasis and tumor progression.
The actin nucleating and polymerizing formin-like 2 (FMNL2) is upregulated in several cancers and has been shown to play important roles in cell migration, invasion, cell–cell adhesion and filopodia formation. Here, using structured illumination microscopy we show that FMNL2 promotes rapid and highly dynamic filopodia formation in epithelial cells while remaining on the tip of the growing filopodia. This filopodia tip localization depends fully on its N-terminal myristoylation. We further show that FMNL2-dependent filopodia formation requires its serine 1072 phosphorylation within the diaphanous-autoregulatory domain (DAD) by protein kinase C (PKC) α. Consistent with this, filopodia formation depends on PKC activity and PKCα localizes to the base of growing filopodia. Thus, a PKCα–FMNL2 signaling module spatiotemporally controls dynamic filopodia formation.
In article number 2204896, a novel role of the formin FMNL2 is uncovered by Dennis Frank, Christel Jessica Moussi, Carsten Schwan, Robert Grosse, and co-workers. TGFβ-induced processes, such as cell invasion and the secretion and trafficking of the pro-metastatic factor ANGPTL4 require phospho-activated FMNL2. Live cell super-resolution microscopy allows the observation of FMNL2 directly polymerizing actin at motile ANGPTL4-containing vesicles. A time course of FMNL2 (green) and actin polymerization (cyan) at an ANGPTL4 vesicle (magenta) is shown, starting from the association of FMNL2 (top left) and ending with the dissociation of the formin (bottom right).
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