Reticular adhesions: A new class of adhesion complex that mediates cell-matrix attachment during mitosis
Preprint posted on December 14, 2017 https://www.biorxiv.org/content/early/2017/12/14/234237
The ability of cells to adhere to their surrounding extracellular matrix is a fundamental feature of metazoan life and cell adhesion regulates virtually every cellular processes including cell proliferation, cell differentiation and cell migration. Loss of cell adhesion often triggers cell death by anoikis. Cell adhesion is classically mediated by adhesion receptors including integrins which connect the extracellular matrix to the intracellular actin cytoskeleton via the recruitment of large cytoplasmic platforms termed adhesion complexes. These adhesive platforms contain a large number of proteins including paxillin, talin and vinculin. During the cell division process, most cells will disassemble these adhesive structures and round-up but remain attached to their substrates via long actin cables. These actin cables serve as a template for the two daughter cells to spread when division is completed. However how these actin cables remain tethered to the substrate during mitosis remained a mystery.
John G. Lock and colleagues1 identified a novel adhesive structure termed reticular adhesions, that are assembled during metaphase and persist during mitosis, and contribute to mitotic cell adhesion. Using a combination of quantitative imaging and mass-spectrometry, the authors define the composition of these reticular adhesion and revealed that these adhesions are rich in integrin β5 but are devoid of most of the typical components found in classical adhesion complexes. Instead, reticular adhesions are enriched in proteins directly or indirectly binding to the phospho-inositide PI(4,5)P2 such as the endocytic adaptors AP2, DAB2 and NUMB. The authors also report that, during interphase, reticular adhesions are disconnected from the actin cytoskeleton. Disruption of these adhesions (by interfering with integrin β5 expression) leads to mitotic defects and loss of spatial memory during re-spreading.
Open Questions for future studies
The discovery made by John G. Lock and colleagues is very exciting as it opens a plethora of novel research avenues in a field where the same molecules have often been studied repeatedly. Below is a list of open questions that I particularly find exciting.
1. What is the role of these structures during interphase?
The authors report that reticular adhesions are prominent during interphase but their functions outside of mitosis remain to be addressed. One key feature of classical adhesion complexes are their ability to exert force and sense stiffness. Could reticular adhesion also be mechanosensitive?
Recently, Elkhatib et al reported that β1 integrin contained in AP2 clathrin lattices contributed to cell migration in 3D collagen outside of its role in classical focal adhesions 2. The reticular adhesions described here are also rich in AP2, clathrin and other endocytosis adaptors. Could reticular adhesions be related to the AP2 lattices described by Elkhatib and colleagues and also contribute to cell migration in 3D environments?
2. Do similar structures exist in vivo?
A key questions that has plagued the adhesion field for nearly two decades is the relevance of adhesive structures observed in 2D to organisms. This is especially important considering that the integrin β5 knockout mouse is viable. Looking for these new structures in vivo and/or in 3D is likely to be of high priority.
3. How do cells stay attached when dividing on non-integrin β5 ligand?
Integrin β5 has a limited ligand binding preference. What are the mechanisms used by cells in environments that contain low amounts or no β5 ligand? Could the answer come from the endocytosis adaptors?
4. How is β5 integrin activity / function regulated in reticular adhesions?
Integrin function is classically modulated by both a conformational shift that regulates receptor-ligand affinity and by intracellular trafficking that determines receptor availability on the plasma membrane. The authors report that most of the classical integrin activity regulators are absent from these reticular adhesions. Interestingly, mass-spectrometry analysis suggest that two integrin activators, talin-2 and tensin-3 3, could be present in these reticular adhesions. In addition several endocytic adaptors were identified. Dab2 and Numb were previously found to associate directly with integrin β5 4, while AP2 was previously found to directly associate with several α integrins 5. Could these proteins or others contribute to integrin β5 function in reticular adhesions?
2. Elkhatib, N. et al. Tubular clathrin/AP-2 lattices pinch collagen fibers to support 3D cell migration. Science 356, (2017).
3. Georgiadou, M. et al. AMPK negatively regulates tensin-dependent integrin activity. J. Cell Biol. 216, 1107–1121 (2017).
4. Calderwood, D. A. et al. Integrin beta cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc. Natl. Acad. Sci. U. S. A. 100, 2272–2277 (2003).
5. De Franceschi, N. et al. Selective integrin endocytosis is driven by interactions between the integrin α-chain and AP2. Nat. Struct. Mol. Biol. 23, 172–179 (2016).
Posted on: 21st February 2018Read preprint
Also in the cell biology category:
ROS production by localized SCHENGEN receptor module drives lignification at subcellular precision
|Selected by||Marc Somssich|
ER membranes exhibit phase behavior at sites of organelle contact
|Selected by||Berrak Ugur|
Lis1 regulates Phagocytosis by co-localising with actin in the Phagocytic cup
|Selected by||Nicola Stevenson|
preListscell biology category:in the
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
|List by||Gautam Dey|
Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.
|List by||Sandra Malmgren Hill|
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
|List by||Rob Hynds|
A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.
|List by||Pablo Ranea Robles|
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
|List by||Gautam Dey|
This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.
|List by||Sandra Franco Iborra|
Biophysical Society Annual Meeting 2019
Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA
|List by||Joseph Jose Thottacherry|
ASCB/EMBO Annual Meeting 2018
This list relates to preprints that were discussed at the recent ASCB conference.
|List by||Gautam Dey, Amanda Haage|