Akt is negatively regulated by Hippo signaling for growth inhibition in Drosophila

Abstract

Tissue growth is achieved through coordinated cellular growth, cell division and apoptosis. Hippo signaling is critical for monitoring tissue growth during animal development. Loss of Hippo signaling leads to tissue overgrowth due to continuous cell proliferation and block of apoptosis. As cells lacking Hippo signaling are similar in size compared to normal cells, cellular growth must be properly maintained in Hippo signaling-deficient cells. However, it is not clear how Hippo signaling might regulate cellular growth. Here we show that loss of Hippo signaling increased Akt (also called Protein Kinase B, PKB) expression and activity, whereas activation of Hippo signaling reduced Akt expression in developing tissues in Drosophila. While yorkie (yki) is sufficient to increase Akt expression, Akt up-regulation caused by the loss of Hippo signaling is strongly dependent on yki, indicating that Hippo signaling negatively regulates Akt expression through Yki inhibition. Consistently, genetic analysis revealed that Akt plays a critical role in facilitating growth of Hippo signaling-defective tissues. Thus, Hippo signaling not only blocks cell division and promotes apoptosis, but also regulates cellular growth by inhibiting the Akt pathway activity.

CD44 acts through RhoA to regulate YAP signaling

“…However, whether YAP acts as an upstream regulator of C-myc, CDKs and Caspase3 to regulate cell proliferation and apoptosis is essential and needs further exploring. Besides, Hippo signaling negatively regulates Akt expression through Yki inhibition in Drosophila [53]. Our results suggested that the function of CD44 in cell proliferation and apoptosis might be related to YAP regulation.…”

The Hippo pathway: regulators and regulations

“…Consistently, knockout of MST1/2 or Sav in the liver or heart also induced organ size (Zhou et al 2009;Lee et al 2010;Lu et al 2010;Song et al 2010;Heallen et al 2011). Recently, a connection between the Hippo pathway and the PI3K-TOR pathway has been demonstrated (Strassburger et al 2012;Tumaneng et al 2012b;Ye et al 2012). This is significant because TOR signaling is important in cell growth; thus, the Hippo pathway may control organ size in part by modulating cell growth ( Fig.…”

Endocytosis of Wingless via a dynamin-independent pathway is necessary for signaling in Drosophila wing discs

“…6K). This finding suggests a delicate balance between growth rates and signaling in generating a normal wing because gross up-regulation or down-regulation of the PI3K pathway simply increases/decreases the size of the wing (47). However, we cannot exclude the possibility that PI3K also affects Wg signaling via Akt repression.…”