Abstract
Cell adhesion to the extracellular matrix or to surrounding cells plays a key role in cell proliferation and differentiation and is critical for proper tissue homeostasis. An important pathway in adhesion-dependent cell proliferation is the Hippo signaling cascade, which is coregulated by the transcription factors Yes-associated protein 1 (YAP1) and transcriptional coactivator with PDZ-binding motif (TAZ). However, how cells integrate extracellular information at the molecular level to regulate YAP1's nuclear localization is still puzzling. Herein, we investigated the role of β1 integrins in regulating this process. We found that β1 integrin-dependent cell adhesion is critical for supporting cell proliferation in mesenchymal cells both in vivo and in vitro β1 integrin-dependent cell adhesion relied on the relocation of YAP1 to the nucleus after the down-regulation of its phosphorylated state mediated by large tumor suppressor gene 1 and 2 (LATS1/2). We also found that this phenotype relies on β1 integrin-dependent local activation of the small GTPase RAC1 at the plasma membrane to control the activity of P21 (RAC1)-activated kinase (PAK) of group 1. We further report that the regulatory protein merlin (neurofibromin 2, NF2) interacts with both YAP1 and LATS1/2 via its C-terminal moiety and FERM domain, respectively. PAK1-mediated merlin phosphorylation on Ser-518 reduced merlin's interactions with both LATS1/2 and YAP1, resulting in YAP1 dephosphorylation and nuclear shuttling. Our results highlight RAC/PAK1 as major players in YAP1 regulation triggered by cell adhesion.
Highlights
Cell adhesion to the extracellular matrix or to surrounding cells plays a key role in cell proliferation and differentiation and is critical for proper tissue homeostasis
We found that 1 integrin– dependent cell adhesion is critical for supporting cell proliferation in mesenchymal cells both in vivo and in vitro. 1 integrin– dependent cell adhesion relied on the relocation of Yesassociated protein 1 (YAP1) to the nucleus after the down-regulation of its phosphorylated state mediated by large tumor suppressor gene 1 and 2 (LATS1/2)
We found that this phenotype relies on 1 integrin– dependent local activation of the small GTPase RAC1 at the plasma membrane to control the activity of P21 (RAC1)-activated kinase (PAK) of group 1
Summary
1 integrins regulate mesenchymal cell proliferation in a MAPK-independent manner. To explore the function of 1 integrins in bone tissue, we inactivated the 1 integrin gene in osteoblasts using Osterixdriven Cre recombinase expression. In good agreement with this, we noticed that the phosphorylation of YAP on Ser-127 (required for 14-3-3 binding) increased upon the deletion of 1 integrins as well as the ratio of activated (phosphorylated) versus total form of LATS (Fig. 3B) Taken together, these data confirmed that 1 integrins are important players in controlling YAP nuclear localization most likely in a LATS-dependent manner. Our data highlighted the important role of YAP signaling in the control of cell proliferation downstream of 1 integrins To confirm this view, we performed unbiased transcriptomic analyses on wild-type and 1 integrin-deficient cells under optimal growth conditions. In contrast to what was measured in 1-deficient cells, the expression of YAP5SA in wild-type cells was able to up-regulate cyclin D2 and down-regulate p19Arf but not p21CIP when compared with control cells (Fig. 3E) This strongly suggests that some important cell-cycle regulators are transcriptionally modified by the YAP–TEAD complex. It is well known that integrins play a critical role in
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