Kim and Gumbiner describe how adhesion to fibronectin can switch off the Hippo signaling pathway and stimulate cell growth.

The Hippo signaling pathway suppresses cell proliferation by activating a protein kinase called Lats that phosphorylates the transcription factors YAP and TAZ, promoting their retention in the cytoplasm. The pathway’s activity is influenced by various factors, including intercellular adhesion and cytoskeletal tension. Mitogens, such as EGF and LPA, inhibit the Hippo pathway by activating PI3-kinase and its downstream target PDK1, allowing YAP/TAZ to enter the nucleus and induce the transcription of progrowth genes. Kim and Gumbiner noticed, however, that, even in the absence of mitogens, PI3-kinase and PDK1 still inhibited Lats and promoted YAP’s entry into the nuclei of subconfluent epithelial cells.

The researchers discovered that, under these conditions, the Hippo pathway was suppressed by the cells’ adhesion to the extracellular matrix protein fibronectin, which activated PI3-kinase via a signaling pathway involving the integrin-associated kinase FAK and its downstream target, Src. Inhibiting FAK or Src reactivated the Hippo pathway and induced YAP’s relocalization to the cytoplasm.

Because integrins and FAK respond to mechanical forces, Kim and Gumbiner’s findings might help explain how cytoskeletal tension modulates Hippo signaling, allowing cell growth to be regulated by the physical properties of the extracellular matrix. The authors now want to investigate how PI3-kinase and PDK1 inhibit the Hippo pathway in response to multiple upstream signals.

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J. Cell Biol.

Author notes

Text by Ben Short