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Monster, J. L.

Publications and source records attributed to Monster, J. L..

4 recordsLinked to original sources

β-Catenin condensation facilitates clustering of the cadherin/catenin complex and formation of nascent cell-cell junctions

Cadherin-based junctions establish dynamically regulated adhesion between cells to coordinate tissue integrity and morphogenetic movements. Adhesion strength can be modulated by the organization of individual cadherin complexes into lateral clusters. Here, we identify a novel clustering mechanism of the cadherin complex established by its core component {beta}-catenin. We show that the disordered termini of {beta}-catenin drive the formation of condensates that incorporate other components of the cadherin complex in vitro. Using {beta}-catenin mutants with hampered condensation, we demonstrate that {beta}-catenin condensation nucleates the formation of submicron cadherin/catenin clusters that further develop into stable sites of adhesion. Furthermore, we show that {beta}-catenin-dependent clustering ensures the efficient formation of de novo cell-cell adhesions. Our data thus indicate a role for {beta}-catenin condensates in the supramolecular organization of the cadherin complex, and reveal that the function of {beta}-catenin in the cadherin complex extends beyond connecting cadherin to -catenin and the actin cytoskeleton.

cell biology↗

Mechanical regulation of cell fate transitions underlying colorectal cancer metastasis formation

Colorectal cancer (CRC) cells exhibit high plasticity and transition between different cellular states during the development of metastasis. Lgr5-expressing cancer stem cells fuel the growth of the primary tumor and metastasis, yet disseminated tumor cells arriving at the metastatic site are devoid of Lgr5 expression. It is currently unknown how CRC cell fate transitions are regulated during the metastatic process and how tumor cells give rise to metastatic lesions despite being Lgr5neg. Here, we show that the reprogramming of disseminating CRC cells is driven by mechanical interactions with the Collagen I-rich interstitial matrix. Collagen I-induced pulling forces are sensed by integrins and mechanosensitive calcium channels, which together direct the transition of CRC cells into a fetal-like state. The fetal-like state is maintained after reaching the blood circulation and promotes metastasis-initiation of disseminated CRC cells in the liver. Our findings indicate a key contribution of mechanical signals in controlling cell fate transitions that underlie the metastatic potential of CRC, involving an interplay between different mechanosensitive mechanisms.

cancer biology↗

CAMSAP-driven microtubule release from γ-TuRC and its regulation by nucleation-promoting factors

{gamma}-tubulin ring complex ({gamma}-TuRC) is the major microtubule-nucleating factor. After nucleation, microtubules can be released from {gamma}-TuRC and stabilized by other proteins, such as CAMSAPs, but the biochemical cross-talk between minus-end regulation pathways is poorly understood. Here, we reconstituted this process in vitro using purified components. We found that all CAMSAP proteins could bind to the minus-ends of {gamma}-TuRC-attached microtubules. CAMSAP2 and CAMSAP3, which decorate and stabilize growing minus ends, but not the minus-end tracking protein CAMSAP1 induced microtubule release from {gamma}-TuRC. CDK5RAP2, a {gamma}-TuRC-interactor, and CLASP2, a regulator of microtubule growth, stimulated {gamma}-TuRC-dependent microtubule nucleation, but only CDK5RAP2 inhibited CAMSAP-driven microtubule detachment by suppressing CAMSAP binding to {gamma}-TuRC-anchored minus ends. CDK5RAP2 also improved {gamma}-TuRC selectivity for 13-rather than 14-protofilament microtubules in microtubule-capping assays. Our results support a model whereby CAMSAPs exploit an imperfect attachment between {gamma}-TuRC and the nucleated microtubule to promote minus-end elongation and release, whereas CDK5RAP2 improves the fit between {gamma}-TuRC and 13-protofilament microtubules and enhances nucleation.

cell biology↗

Systematic analysis of the molecular architecture of endocytosis reveals a nanoscale actin nucleation template that drives efficient vesicle formation

Clathrin-mediated endocytosis is an essential cellular function in all eukaryotes that is driven by a self-assembled macromolecular machine of over 50 different proteins in tens to hundreds of copies. How these proteins are organized to produce endocytic vesicles with high precision and efficiency is not understood. Here, we developed high-throughput superresolution microscopy to reconstruct the nanoscale structural organization of 23 endocytic proteins from over 100,000 endocytic sites in yeast. We found that proteins assemble by radially-ordered recruitment according to function. WASP family proteins form a circular nano-scale template on the membrane to spatially control actin nucleation during vesicle formation. Mathematical modeling of actin polymerization showed that this WASP nano-template creates sufficient force for membrane invagination and substantially increases the efficiency of endocytosis. Such nanoscale pre-patterning of actin nucleation may represent a general design principle for directional force generation in membrane remodeling processes such as during cell migration and division.

cell biology↗