Importance of the filamin A-Sav1 interaction in organ size control: evidence from transgenic mice

Abstract

The nucleocytoplasmic translocation of yes-associated protein 1 (YAP1) controls the growth of animal tissues and organs. YAP1 binds to transcription factors in the nucleus to activate the transcription of proliferation and anti-apoptotic genes. The Hippo pathway prevents the nuclear translocation of YAP1 by phosphorylating YAP1, while mechanical forces promote it by opening the nuclear pore complex and stimulating other signaling pathways. Recently we found that Protein salvador homolog 1 (SAV1), a component of the Hippo pathway, interacts with filamin A (FLNA) in a force-dependent manner, raising a possibility that the Hippo pathway is regulated by mechanical force through the FLNA-SAV1 axis. To test this hypothesis, we generated conditional knock-in (KI) mice expressing non-Flna-binding mutant Sav1 in hepatocytes by crossing with mice carrying Cre recombinase driven by the serum albumin (alb) gene promoter. Unexpectedly, the insertion of the flox cassette skipped exon 2, resulting in a shorter Sav1 in all the transgenic mice. Since exon 2 encodes a fragment containing a Flna-binding domain, we analyzed both point mutant KI and exon 2-deleted mutant mice. Here we show that disruption of the Flna-Sav1 interaction in the mouse liver promotes apoptosis and suppresses tissue and organ growth without affecting the phosphorylation level of Yap1. These results provide evidence that the growth of animal tissues and organs is regulated by apoptosis downstream of the force-dependent FLNA-SAV1 interaction, at least in part.