Integrin and syndecan signalling

Integrin and syndecan signalling

Cell migration during developmental, repair and disease processes is critically dependent on interaction with the extracellular matrix (ECM). Focal adhesions are dynamic sites of contact at the cell-ECM interface that serve as points of integration between the ECM and cytoskeleton and as coordinating nexuses of signalling events. Precise spatio­temporal control of focal adhesion dynamics is essential to permit efficient cell migration, regulating both locomotive cellular traction and the signals that dictate directionality.

Syndecan-4 cytoplasmic domain

Syndecan-4 cytoplasmic domain

PDB entry 1EJP

General introduction

Integrin and syndecan signalling – general intro

Integrin and syndecan signalling: the compass of the cell

Written by Hellyeh Hamidi and Mark Morgan

Cells have many different types of sensing molecules located on their surface. Each sensor has a distinct role, be it anchoring the cell in place, letting the cell explore its surroundings or communicating with neighbouring cells. Together, these sensors provide the cell with vast amounts of information about its environment. The cell must then decode, translate and respond to this information.

One example of a cell sensor is syndecan-4. A large part of the arm-like syndecan-4 molecule is on the outside surface of the cell, where it uses its huge, sticky, sugar-coated “hands” to sense and attach to the cell’s surroundings.

The environment in which a cell lives is known as the extracellular matrix.

Syndecan-4 has a specific role in healing wounds. We know this because mice that lack the syndecan-4 sensor have difficulties making new blood vessels at the site of an injury, and they do not close their wounds as efficiently as normal mice. We have shown that syndecan-4 works in coordination with another sensing molecule on the surface of the cell, the integrin. Together, syndecan-4 and integrin control the ability of a cell to stick to and move across the extracellular matrix.

We believe that syndecan-4 may be acting like a compass, directing which way the cell goes. If we delete the syndecan-4 gene so that it is no longer present on the cell surface, the cell no longer has a single front and tail but instead has several at the same time. The cell becomes confused, and it moves around in circles rather than following a straight path. This may explain why mice lacking syndecan-4 have problems closing a wound. Our research aims to discover how the information collected by syndecan-4 is decoded within the cell and how syndecan-4 works in combination with integrins to cause the cell to change its shape, to move and to close a wound.

General introduction

Integrin and syndecan signalling – general intro

Integrin and syndecan signalling: the compass of the cell

Written by Hellyeh Hamidi and Mark Morgan

Cells have many different types of sensing molecules located on their surface. Each sensor has a distinct role, be it anchoring the cell in place, letting the cell explore its surroundings or communicating with neighbouring cells. Together, these sensors provide the cell with vast amounts of information about its environment. The cell must then decode, translate and respond to this information.

One example of a cell sensor is syndecan-4. A large part of the arm-like syndecan-4 molecule is on the outside surface of the cell, where it uses its huge, sticky, sugar-coated “hands” to sense and attach to the cell’s surroundings.

The environment in which a cell lives is known as the extracellular matrix.

Syndecan-4 has a specific role in healing wounds. We know this because mice that lack the syndecan-4 sensor have difficulties making new blood vessels at the site of an injury, and they do not close their wounds as efficiently as normal mice. We have shown that syndecan-4 works in coordination with another sensing molecule on the surface of the cell, the integrin. Together, syndecan-4 and integrin control the ability of a cell to stick to and move across the extracellular matrix.

We believe that syndecan-4 may be acting like a compass, directing which way the cell goes. If we delete the syndecan-4 gene so that it is no longer present on the cell surface, the cell no longer has a single front and tail but instead has several at the same time. The cell becomes confused, and it moves around in circles rather than following a straight path. This may explain why mice lacking syndecan-4 have problems closing a wound. Our research aims to discover how the information collected by syndecan-4 is decoded within the cell and how syndecan-4 works in combination with integrins to cause the cell to change its shape, to move and to close a wound.

Scientific details

Integrin and syndecan signalling – scientific details

Cell migration during developmental, repair and disease processes is critically dependent on interaction with the extracellular matrix (ECM). Focal adhesions are dynamic sites of contact at the cell-ECM interface that serve as points of integration between the ECM and cytoskeleton and as coordinating nexuses of signalling events. (See: Cell-ECM interactions in Scientific image galleries for a selection of images.) Precise spatiotemporal control of focal adhesion dynamics is essential to permit efficient cell migration, regulating both locomotive cellular traction and the signals that dictate directionality.

The cell-surface receptors that mediate cell-ECM adhesion are primarily members of two gene families: the integrins and the syndecans. Nearly all ECM molecules contain binding sites for both types of receptor, and there is strong evidence that a full cell-adhesion response requires engagement of both receptor types. Thus, ligation of both integrin and syndecan receptors is required for focal adhesion formation and directionally persistent migration, and perturbation of both receptor families leads to substantial wound healing defects. Interestingly, syndecans also function as co-receptors for growth factors, morphogens and cytokines, which suggests that they may play an important role in coordinating both matrix-associated and secreted environmental signals.

While mechanisms of direct integrin-syndecan crosstalk have not yet been identified, analyses in vitro have demonstrated clear synergy between signalling cascades downstream of the two receptor families. We believe that this synergistic signalling plays a fundamental role in microenvironmental sensing and the regulation of cell migration.

We are specifically interested in the mechanisms by which these two receptor families regulate each others function in order to spatially and temporally coordinate focal adhesion dynamics, GTPase activity and cell migration.

We have previously shown that syndecan-4 engagement is required to control activation of the small GTPase Rac1 in order to regulate directional cell migration and that p190RhoGAP is at least one of the convergence points downstream of syndecan-4 and α5β1 integrin involved in GTPase regulation. The role of syndecan-4 engagement in precisely coordinating these signalling events is fundamental to the regulation of focal adhesion dynamics and the promotion of efficient cell migration.

Further reading

Integrin and syndecan signalling – further reading

MD Bass, MR Morgan, KA Roach, J Settleman, AB Goryachev and MJ Humphries (2008) p190RhoGAP is the convergence point of adhesion signals from α5β1 integrin and syndecan-4. J. Cell Biol. 181: 1013-26. Full text | PubMed entry

MR Morgan, MJ Humphries and MD Bass (2007) Synergistic control of cell adhesion by integrins and syndecans. Nat. Rev. Mol. Cell Biol. 8: 957-69. Full text | PubMed entry

MD Bass, KA Roach, MR Morgan, Z Mostafavi-Pour, T Schoen, T Muramatsu, U Mayer, C Ballestrem, JP Spatz and MJ Humphries (2007) Syndecan-4-dependent Rac1 regulation determines directional migration in response to the extracellular matrix. J. Cell Biol. 177: 527-38. Full text | PubMed entry

Integrin and syndecan signalling – right hand column

Syndecan-mediated coordination of receptor signalling | Image by Mark Bass

Related galleries

  • Cell-ECM interactions gallery
  • Actin cytoskeleton gallery
  • Microtubule cytoskeleton gallery

See: Scientific image galleries