You are here : Home > Scientific news > Spatial organization of growth factor receptors in anchoring zones of a cell

Highlight | Cellular mechanisms

Spatial organization of growth factor receptors in anchoring zones of a cell

What is the spatial arrangement of growth factor receptors at the cell surface to sense physical and biochemical signals from the extracellular matrix?
By combining high-resolution microscopy, dynamic imaging, optogenetics and biomaterials, researchers at IAB and IRIG were able to localize growth factor receptors in anchoring areas of the cell to coordinate cell adhesion and differentiation processes.

Published on 21 December 2022

​The organization of cell-surface receptors is fundamental to coordinate the biological responses of cells in response to physical and biochemical signals from the extracellular matrix. Indeed, proteins in the extracellular matrix transmit multiple signals to cells in a time-regulated and spatially structured manner. 

For example, fibronectin, one of the main proteins of the matrix, has binding sites close enough to establish interactions with integrin adhesive receptors and with growth factors. This property allows a functional juxtaposition between integrins and growth factor receptors. 
Previous work showed that the growth factor Bone Morphogenetic Protein 2 (BMP2), presented by a soft matrix, induces cell spreading. This spreading is associated with the formation of adhesive structures that depend on integrin receptors. However, the mechanisms and temporal events that enable concerted responses between integrin receptors and growth factor receptors remained poorly explored. 

Researchers at Irig and IAB have been studying for 15 years how BMP-2 growth factor receptors cooperate with integrins, under the effect of BMP2, to drive cell adhesion and migration. Their recent work has highlighted the cooperation between integrins, which are receptors involved in tissue mechanics, and growth factor receptors, which are of the tyrosine kinase type (named ALK3 and BMPR2) involved in cell differentiation. ALK3/BMPR2 receptors are described to form complexes on the cell surface when they bind to the growth factor BMP2 (see figure). 

This finding shows that the ALK3 receptor exists as two populations distributed inside and outside the adhesion sites in response to BMP2 growth factor. Thus, a first population is associated with integrin and a second forms a complex with BMPR2 receptor. The spatial and temporal recruitment of ALK3 in integrin-based adhesion sites is a key aspect of the control of BMP-2 receptor-induced signaling. The partitioning of ALK3 outside and within adhesion sites provides a new mechanism to control the diversity of BMP signaling and couple cell functions. 

For this study, biologists modified growth factor receptors to control their localization by light (optogenetics) and to monitor their diffusion and confinement properties at the nanoscale. 
The combination of biomaterials with the optogenetic approach allowed to highlight that the proximity between integrins and growth factor receptors was sufficient to trigger cell spreading and to optimize cell differentiation.  Biomaterial-mediated presentation of BMP2 allows spatial proximity between integrins and growth factor receptors, thereby promoting their cooperation. 

Understanding the organization and spatial segregation of growth receptors is of pathophysiological interest as these receptors are described as tumor promoters or suppressors.

Figure : © Corinne Albiges-Rizo (CNRS)
BMP2 induces redistribution of ALK3 receptor at the cell surface as two populations: one is sequestered in the integrin-mediated adhesion site; the other is immobilized in the plasma membrane outside the anchoring zones (FA), likely through its association with the BMPRII receptor. 
The fibronectin matrix provides a binding site for integrin (domain 7-10) and a binding site for BMP2 (domain 12-14) promoting proximity between ALK3 and β3 integrin in adhesion sites. BMP2-induced Smad signaling requires ALK3, BMPRII, and β3 integrins, whereas cell adhesion processes (spreading and migration) rely solely on ALK3 and β3 integrins. The biomaterials developed at IRIG have the characteristic of presenting BMP2 which promotes the cooperation between integrins and growth factor receptors.

Optogenetics is a combination of optical and genetic techniques. Cells are genetically modified to express a photosensitive protein that activates at a specific location in the cell when illuminated with light.

Integrin is a transmembrane receptor involved in cell adhesion and mechanics. The structure comprises (1) an extracellular part recognizing proteins of the extracellular matrix and (2) an intracellular part connected to the cytoskeleton of the cell.

Top page

Top page