Human angiomotin‐like 1 associates with an angiomotin protein complex through its coiled‐coil domain and induces the remodeling of the actin cytoskeleton

Abstract

Angiostatin is a potent inhibitor of angiogenesis. One mechanism through which angiostatin inhibits angiogenesis is by binding to the cell surface protein p80-angiomotin. The p80-angiomotin protein promotes angiogenesis, in part, by conferring a hypermigratory phenotype to endothelial cells. Although p80-angiomotin is extensively characterized, less is known about the related protein angiomotin-like 1. We report that angiomotin-like 1 forms part of a protein complex containing p80-angiomotin. Structure-function studies revealed that angiomotin-like 1 associates with this p80-angiomotin-containing complex via its coiled-coil domain. Since p80-angiomotin plays a role in cell migration, a process that involves the remodeling of the actin cytoskeleton, we then addressed the hypothesis that angiomotin-like 1 may interact with the cytoskeleton. Immunofluorescence studies reveal that angiomotin-like 1 not only co-localizes with filamentous actin but also significantly modifies the architecture of the actin cytoskeleton. Regarding migration, angiomotin-like 1 increases the velocity of migration and decreases the persistence of migration directionality. Together these observations strongly suggest that angiomotin-like 1 is involved in actin-cytoskeleton-based processes, in part, via its interaction with a p80-angiomotin-containing complex and the actin cytoskeleton. These findings have important implications for angiogenesis-driven disease since angiomotin and angiomotin-like 1 are both expressed in capillaries.

Hippo pathway regulation by cell morphology and stress fibers

“…F-actin probably functions as a scaffold for Hippo pathway components, and interactions with Factin regulate signaling. Indeed, several Hippo pathway components, including Mst1/2 (Densham et al, 2009), merlin/NF2 (McCartney et al, 2000) and Amot (Ernkvist et al, 2006;Gagne et al, 2009), bind to actin, and Mst1/2 is activated upon F-actin depolymerization (Densham et al, 2009). …”

Angiomotin-like Proteins Associate with and Negatively Regulate YAP1

“…These three proteins belong to a new protein family with a highly conserved coil-coil domain, PDZ binding domain, and glutamine-rich domain (24). Just like AMOT, AMOTL1 and AMOTL2 also play important roles in cell migration and angiogenesis (26,27), suggesting that this family of proteins may share similar functions in vivo.…”

The Amotl2 Gene Inhibits Wnt/β-Catenin Signaling and Regulates Embryonic Development in Zebrafish

“…These proteins have been demonstrated to play important roles in angiogenesis, cell mobility, cell polarity, and cell-cell junctions by regulating distinct signaling pathways (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). Interestingly, it appears that each Motin family member in human and mice has two isoforms, long and short isoform (14), which function differently in physiological processes (17,(25)(26)(27)(28). However, it is unknown whether Motin members participate in regulation of canonical Wnt signaling pathway.…”