Src mediates β-adrenergic receptor induced YAP tyrosine phosphorylation

The Hippo pathway is a newly identified pathway and evolutionarily conserved from flies to humans mainly regulating cell proliferation. Transcriptional co-activator Yes-associated protein (YAP) functions as a major downstream effector and key node of the Hippo pathway. Phosphorylation of YAP is critical to regulate YAP activity and its corresponding functions. β-adrenergic receptor (β-AR), a typical G protein coupled receptor (GPCR), mediates proliferation in various cell types and regulates multiple physical and pathological processes. However, the role of β-AR in regulating YAP remains elusive. Here, we report that β-AR can obviously stimulate YAP tyrosine phosphorylation. The mechanism is that β-AR stimulation results in tyrosine kinase Src activation and Src phosphorylates YAP tyrosine at Y³⁵⁷. Further studies demonstrate that inhibition of Src kinase activity can obviously alleviate β-AR induced YAP tyrosine phosphorylation and cell proliferation. We conclude that β-AR can induce YAP tyrosine phosphorylation and also establish the Src/YAP pathway as a critical signaling branch downstream of GPCR.