Intrinsic cell rheology drives junction maturation

Journal article

Spatiotemporal control of adherens junction fluidity and integrity is critical for sprouting angiogenesis, but underlying mechanisms are incompletely understood. To identify unappreciated regulators of VE-cadherin, we performed proximity ligation mass spectrometry, revealing significant interaction with the multifunctional scaffold Scribble (Scrib). Utilizing a 3D angiogenesis-on-chip model, I discover that SCRIBKO microvessels display reduced multicellular sprouting and increased single-cell detachments that are associated with adherens junction instability and decreased actomyosin in the junction-proximal cortex. I find that this disruption is not due to defects in VE-cadherin coupling to catenins or actin. Instead, SCRIBKO causes loss of cortical actomyosin clusters, which organize cortical actomyosin architecture and dynamics to stabilize adherens junctions. Moreover, I discover that unconventional myosin 1c is a critical effector linking Scrib cortical dynamics to VE-cadherin to regulate stabilization of adherens junctions during angiogenic initiation. This work demonstrates a new role for Scrib directly regulating cortical actomyosin cluster organization, critical for precise control of adherens junctions during angiogenesis. The thesis illustrates how engineered models of the vasculature can reveal novel cell biology underlying morphogenetic mechanisms. I review how the implementation of such models has also uncovered new mechanisms of vascular-tumor interactions during metastasis

Authors: Sri-Ranjan, K; Sanchez-Alonso, JL; Swiatlowska, P; Rothery, S; Novak, P

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 13
• Issue: 1
• Pages: 4832-4832
• Article number: 4832
• Publication date: 2022-08-17
• DOI: 10.1038/s41467-022-32102-9
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Cell adhesion; Materials science; Genetics; Stiffness; Cell junction; Adhesion; Biology; Biophysics; Actin; Cell biology; Composite material; Elasticity (physics); Rheology; Cell