α-Catenin phosphorylation under tension recruits Afadin to epithelial junctions in cells and mice
Northwestern University researchers showed that mechanical force triggers α-catenin phosphorylation, which lets it bind Afadin and support the epithelial barrier in cultured cells and mice.
A team led by Cara J. Gottardi, professor of medicine in pulmonary and critical care at Northwestern University, reported in The Journal of Cell Biology how the protein α-catenin responds to mechanical force at junctions between epithelial cells. Experiments were carried out in cultured cells and in mice. Under tension, α-catenin is chemically modified, and this modification allows it to recruit the scaffold protein Afadin doi.org
The Journal of Cell Biologydoi.orgOpen source ↗.
Epithelial cells line organs and tissues and form a protective barrier. The barrier depends on the ability of cells to stay attached to one another and to limit gaps that leave tissue vulnerable to infection and inflammation, Gottardi noted. How the protein links between neighbouring cells react to dynamic forces in living tissue has remained poorly understood.
Force-dependent phosphorylation of α-catenin
Zonula adherens junctions (zAJ) sit close to tight junctions in a structure called the apical junctional complex, which includes a circumferential ring of filamentous actin. The authors show that α-catenin, a mechanosensitive component of zAJ, is phosphorylated in an unstructured linker region in a force-dependent manner. This phosphorylation primes the mechanosensitive Middle-region of α-catenin for binding to effector proteins.
The authors identify Afadin, a multi-domain scaffold protein of tight and adherens junctions, as a mechano-chemical binding partner of α-catenin. They also identify the residues in α-catenin required for this interaction doi.org
The Journal of Cell Biologydoi.orgOpen source ↗.
Consequences for the epithelial barrier
Phosphorylation of α-catenin and its binding to Afadin are both required for the two proteins to co-enrich at zAJ and for epithelial barrier function. In mice carrying an α-catenin mutation that blocks binding to Afadin, visible gaps appeared between epithelial cells and barrier function was impaired, according to the summary of the work.
A mouse model that prevents α-catenin phosphorylation proved particularly detrimental to post-natal brain development. The data support a stepwise model in which α-catenin integrates mechanical and chemical signals to promote zAJ enrichment, effector recruitment and barrier function.
According to Gottardi, mechanical unfolding alone is not enough: the protein uses both unfolding and chemical modification to organise itself and its partners into tight junctions. She describes α-catenin as a force-sensitive molecular switch.
