New tools to study the interaction between integrins and latent TGFβ1

Area of Science:

• Cell biology
• Biochemistry
• Integrin signaling

Background:

• Transforming growth factor beta (TGFβ) 1 is a key regulator of cell functions, implicated in fibrosis and tumor immunity.
• Integrin αVβ6 activates latent TGFβ1 by applying mechanical force to its latency-associated peptide (LAP).
• The cytoplasmic mechanisms enabling integrin-mediated force application on LAP remain poorly understood.

Approach:

• Developed novel tools, including a chimeric protein (sLAP1), combining LAP1 with GFP and an IgG Fc chain.
• Investigated the mechanical rearrangement of immobilized sLAP1 upon binding to integrin αVβ6.
• Assessed integrin αVβ6 binding to LAP2 and LAP3 using respective chimeric proteins (sLAP2, sLAP3).

Key Points:

• Integrin αVβ6 induced a unique mechanical rearrangement of sLAP1, an interaction not seen with other integrins.
• Integrin αVβ6 exhibited differential binding affinities and rearrangement capabilities with LAP1, LAP2, and LAP3.
• The αVβ6-sLAP1 interaction remained robust under conditions of reduced cellular contractility.

Conclusions:

• Reveals a specific mechanical linkage between integrin αVβ6 and latent TGFβ1 via LAP1.
• Highlights distinct binding and force-transducing properties of αVβ6 with different LAP isoforms.
• Suggests a unique mechanism for TGFβ1 activation mediated by αVβ6, independent of global cellular tension.