Professor Sonnenberg, the head of the Division of Cell Biology at the Netherlands Cancer Institute located in Amsterdam, is a specialist in the field of integrin research with. Deciphering the function of integrins in migration and differentiation, and the role of integrins and associated proteins in the regulation of the assembly of multiprotein complexes in normal and pathological conditions is his primary aim.
Integrins, associated proteins and disease
Integrins are a group of cell surface transmembrane receptors, each comprising of an α and a β subunit binding to extracellular matrix (ECM) proteins and cellular counter receptors and identify with the cytoskeleton.
In mammals, 24 different integrins are produced through various combinations of 18 α and 8 β subunits. A majority of the integrins bind to the actin cytoskeleton and exist in adhesion structures, known as focal adhesions, whereas integrin α6β4 attaches to the intermediate filament (IF) system and is localized in hemidesmosomes.
"Inside-out" and "outside-in" signaling
The binding of integrins to the actin cytoskeleton is indirect and includes multiple adaptor molecules. Two of which, kindlin and talin, attach directly to the cytoplasmic domain of the integrin β subunit and play a major role in the regulation of integrin affinity (“inside-out” activation).
Conformational rearrangement of the extracellular and intracellular domains regulates integrin affinity for adhesive ligands. The “outside-in” signaling process involves the use of integrins to recruit cytoskeletal proteins to sites of cell-ECM contacts, thus driving integrin clustering and promoting the generation of focal adhesions.
Adaptor molecules: talin and kindlin
Although direct binding to actin is possible for talin, binding of vinculin is required for a secure connection to the actin cytoskeleton. However, kindlin establishes a connection to the actin cytoskeleton through ILK, which is an element of a complex comprising of PINCH and parvin, an actin-binding protein.
Also, kindlin, along with migfilin and filamin, forms a complex to encourage integrin binding to the actin cytoskeleton. Since these cytoskeletal proteins can bind actin filaments, they may influence integrin clustering and/or the stabilization of clustered integrins, thereby regulating integrin activity.
Besides establishing a structural link between the actin cytoskeleton and the ECM, focal adhesions are also key hubs for the transmission of mechanical force and biochemical signals controlling diverse processes such as cell division, cell migration, and cell survival.
Major players in focal adhesions are non-receptor kinases (FAK and Src) and adaptor proteins (paxillin, Crk, Cas).
The association of α6β4 with IFs takes place via the cytoskeletal linker protein plectin and the cytoplasmic domain of β4. The association of β4 with plectin includes the actin-binding domain (ABD) of plectin and restricts its association with actin.
The binding of α6β4 with plectin is a key process in the assembly of hemidesmosomes as the complex formed functions as a scaffold on which the assembly of other hemidesmosomal proteins (bullous pemphigoid (BP) antigens 180 and 230) takes place.
Tetraspanins and cell adhesion to laminin
Integrins not only bind to cytoskeletal proteins but can also take part in lateral binding to members of the tetraspanin-4 family. Tetraspanins produce functional microdomains (tetraspanin webs) via self-binding and binding to other tetraspanins.
The binding of the laminin-binding integrins (α3β1, α6β1, α6β4 and α7β1) to the tetraspanin CD151 supports cell adhesion through mechanisms including integrin clustering in the plasma membrane. In addition, CD151 can organize α6β4 into multiprotein complexes, thus promoting hemidesmosome assembly.
The importance of integrins in human disease
Numerous congenital disorders have been linked to defective integrin-mediated adhesion. These include muscular dystrophy (integrin α7β1 in striated muscle), nephrotic syndrome and interstitial lung disease (integrin α3β1 in glomerular and alveolar epithelial cells), leukocyte adhesion deficiency-I (β2 integrins in leukocytes) and -III (kindlin-3), the bleeding disorder Glanzmann’s thrombasthenia (integrin αIIbβ3 in platelets), and the blistering disorder junctional epidermolysis bullosa (integrin α3β1 and kindlin-1, and integrin α6β4 and plectin in keratinocytes).
Moreover, several αv integrins, αvβ6 in particular, play an important part in the control TGFβ activity in fibrosis, while αvβ3 is linked to tumor progression and angiogenesis.
α2β1, α3β1, α5β1, α6β1 and α6β4 are the other integrins implicated in cancer development and invasion. Much of current work evaluates the significance of integrins and their downstream signaling events in the treatment of various diseases, including different types of cancers, fibrosis, and inflammation.
- Litjens, S.H.M., de Pereda, J.M., and Sonnenberg, A. Current insights into the formation and breakdown of hemidesmosomes. Trends Cell Biol. 16:376-383 (2006).
- Margadant, C., and Sonnenberg, A. Integrin-TGFβ crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 11: 97-105 (2010).
- Margadant, C., Charafeddine, R.A., and Sonnenberg, A. Unique and redundant functions of integrins in the epidermis. FASEB J. 24: 4133-4152 (2010).
- Nicolaou, N., Margadant, C., Kevelam, S.H., Lilien, M.R., Oosterveld, M.J.S., Kreft, M., van Eerde, A.M., Pfundt, R., Terhal, P.A., van der Zwaag, B., Nikkels, P.G., Sachs, N., Goldschemding, R., Knoers, N.V.A.M., Renkema, K., Y., and Sonnenberg, A. Gain-of-glycosylation in integrin α3 causes lung disease and nephrotic syndrome. J. Clin. Invest. 122: 4375-4387 (2012).
- Sachs, N., Claessen, N., Aten, J., Kreft, M., Teske, G.J.D., Koemann, A., Zuurbier, C.J., Janssen, H., and Sonnenberg, A. Blood pressure influences end-stage renal disease of Cd151 knockout mice. J. Clin. Invest. 122: 348-358 (2012).
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