Abstract
The Hippo pathway controls organ growth and is implicated in cancer development. Whether and how Hippo pathway activity is limited to sustain or initiate cell growth when needed is not understood. The members of the AJUBA family of LIM proteins are negative regulators of the Hippo pathway. In mammalian epithelial cells, we found that AJUBA LIM proteins limit Hippo regulation of YAP, in proliferating cells only, by sequestering a cytosolic Hippo kinase complex in which LATS kinase is inhibited. At the plasma membranes of growth-arrested cells, AJUBA LIM proteins do not inhibit or associate with the Hippo kinase complex. The ability of AJUBA LIM proteins to inhibit YAP regulation by Hippo and to associate with the kinase complex directly correlate with their capacity to limit Hippo signaling during Drosophila wing development. AJUBA LIM proteins did not influence YAP activity in response to cell-extrinsic or cell-intrinsic mechanical signals. Thus, AJUBA LIM proteins limit Hippo pathway activity in contexts where cell proliferation is needed.
Highlights
Proliferating metazoan cells, upon formation of a complete organ in vivo, undergo growth arrest or cessation of proliferation, which is critical for the ultimate determination of organ size during development
When AJUBA and LIMD1, two of the three mammalian AJUBA LIM proteins, were RNA interference (RNAi) depleted individually, there was no significant change in the pS127.YAP level or YAP transcriptional activity in cells at low density (LD) or high density (HD) (Fig. 1C and F)
Our results indicate that the AJUBA LIM proteins limit Hippo pathway-mediated YAP inactivation in proliferating cells
Summary
Proliferating metazoan cells, upon formation of a complete organ in vivo, undergo growth arrest or cessation of proliferation, which is critical for the ultimate determination of organ size during development. The upstream signals activating the Hippo pathway, which leads to phosphorylation and inactivation of YAP and cessation of proliferation, are diverse and can involve distinct intracellular signaling cascades. They include changes in cell-cell contact, cell polarity, cell tension, anoikis, and hormonal signals [9,10,11,12,13,14]. Members of the AJUBA family of LIM domain-containing proteins inhibit Hippo signaling at the level of the core kinases [20]. Hippo Pathway Inhibition by AJUBA LIM Proteins precise environmental or developmental signal or context that influences their activity, and how, is not fully understood
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