All tags Cancer Integrins and associated proteins

Integrins and associated proteins

by Professor Arnoud Sonnenberg

Professor Sonnenberg, head of the Division of Cell Biology at the Netherlands Cancer Institute in Amsterdam, is an expert in the field of Integrin research. His main objective is to decipher the function of integrins in differentiation and migration, and how integrins and associated proteins regulate the assembly of multiprotein complexes in normal and pathological conditions.

Integrins, associated proteins and disease

Integrins are a family of cell surface transmembrane receptors, each consisting of an α and a β subunit that bind to extracellular matrix (ECM) proteins and cellular counter receptors and associate with the cytoskeleton.

In mammals, 24 different integrins are generated through different combinations of 18 α and 8 β subunits.

While most integrins connect to the actin cytoskeleton and reside in adhesion structures, called focal adhesions, integrin α6β4 connects to the intermediate filament (IF) system and is localized in hemidesmosomes.

"Inside-out" and "outside-in" signaling

The association of integrins with the actin cytoskeleton is indirect and involves a number of adaptor molecules. Two of these, talin and kindlin, bind directly to the cytoplasmic domain of the integrin β subunit and are key regulators of integrin affinity (“inside-out” activation).

Integrin affinity for adhesive ligands is regulated by conformational rearrangement of the intracellular and extracellular domains. In a process called “outside-in” signaling, the engagement of integrins results in the recruitment of cytoskeletal proteins to sites of cell-ECM contacts, thereby promoting integrin clustering and driving the formation of focal adhesions.

Adaptor molecules: talin and kindlin

Although talin can bind directly to actin, binding of vinculin is necessary for strong connection to the actin cytoskeleton. On the other hand, kindlin connects to the actin cytoskeleton via ILK, which is part of a complex consisting of PINCH and the actin-binding protein parvin.

Kindlin can also form a complex with migfilin and filamin to promote integrin binding to the actin cytoskeleton. Through their ability to bind actin filaments, these cytoskeletal proteins may influence the clustering of integrins and/or the stabilization of clustered integrins and thus regulate integrin activity.

Signal transmission

In addition to forming a structural link between the ECM and the actin cytoskeleton, focal adhesions are also important hubs for the transmission of mechanical force and biochemical signals that control diverse processes such as cell migration, cell division and cell survival.

Key players in focal adhesions include adaptor proteins (paxillin, Crk, Cas) and non-receptor kinases (FAK and Src).

Integrin α6β4

The binding of α6β4 to IFs occurs through the cytoskeletal linker protein plectin and the cytoplasmic domain of β4. Binding of β4 to plectin involves the actin-binding domain (ABD) of plectin and prevents its association with actin.

The association of α6β4 with plectin is a crucial step in the assembly of hemidesmosomes as the formed complex functions as a scaffold on which other hemidesmosomal proteins (bullous phemphigoid (BP) antigens 180 and 230) are assembled.

Tetraspanins and cell adhesion to laminin

Integrins not only associate with cytoskeletal proteins, but they can also engage in lateral associations with members of the tetraspanin-4 family. Tetraspanins form functional microdomains (tetraspanin webs) through self association and association with other tetraspanins.

The association of the laminin-binding integrins (α3β1, α6β1, α6β4 and α7β1) with the tetraspanin CD151 strengthens cell adhesion through mechanisms that include the clustering of the integrins in the plasma membrane. Furthermore, the ability of CD151 to organize α6β4 into multiprotein complexes may promote hemidesmosome assembly.

The importance of integrins for human disease

A number of human congenital disorders have been associated with defective integrin-mediated adhesion, including the blistering disorder junctional epidermolysis bullosa (integrin α3β1 and kindlin-1, and integrin α6β4 and plectin in keratinocytes), the bleeding disorder Glanzmann’s thrombastenia (integrin αIIbβ3 in platelets), leukocyte adhesion deficiency-I (β2 integrins in leukocytes) and -III (kindlin-3), nephrotic syndrome and interstitial lung disease (integrin α3β1 in glomerular and alveolar epithelial cells) and muscular dystrophy (integrin α7β1 in striated muscle).

Furthermore, several αv integrins, especially αvβ6, play a key role in the control TGFβ activity in fibrosis, while αvβ3 is associated with angiogenesis and tumor progression.

Other integrins that have been implicated in cancer growth and invasion are α2β1, α3β1, α5β1, α6β1 and α6β4. Much of current work is focused on testing the importance of integrins and their downstream signaling events in the treatment of a variety of diseases, including different types of cancers, inflammation and fibrosis.

References

  • 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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