YAP mediates apoptosis through failed integrin adhesion reinforcement.

Area of Science:

• Cell Biology
• Biophysics
• Biochemistry

Background:

• Extracellular matrix (ECM) rigidity significantly influences cell fate decisions, impacting processes like proliferation.
• While the role of Yes-associated protein (YAP) in cell proliferation on stiff matrices is established, its function in apoptosis induction on soft matrices remains unclear.

Purpose of the Study:

• To elucidate the mechanism by which YAP regulates apoptosis in response to varying extracellular matrix rigidity.
• To investigate the role of YAP phosphorylation and localization in mediating cell fate decisions on soft versus stiff matrices.

Main Methods:

• Analysis of YAP localization and phosphorylation at the Y357 residue in cells cultured on matrices of differing rigidities.
• Investigation of the impact of actomyosin contractility modulation on YAP signaling and cell fate.
• Microscopy and biochemical assays to assess cell adhesion dynamics and nuclear translocation of YAP.

Main Results:

• On soft matrices, YAP is recruited to small adhesions, phosphorylated at Y357, and translocates to the nucleus, promoting apoptosis.
• Conversely, stiff matrices exhibit low Y357 phosphorylation levels in large adhesions, correlating with cell proliferation.
• Reduced actomyosin contractility on soft matrices facilitates adhesion growth, decreases Y357 phosphorylation, and promotes cell growth.

Conclusions:

• Failed adhesion reinforcement on soft matrices drives YAP-mediated, rigidity-dependent apoptosis.
• Cell fate decisions are determined not solely by ECM rigidity but by the interplay between cellular forces and matrix stiffness.
• YAP plays a dual role in cell fate, regulating both proliferation on stiff matrices and apoptosis on soft matrices.