Research interest
The main objective of my group is to study the mechanisms involved in cell adhesion. Specifically, we are interested in understanding the significance of and characterizing the interaction that takes place between cells and the extracellular matrix component laminin. We have shown that the integrin a6b1 is a receptor for laminin-111, as well as for various tissue-specific isoforms of this molecule. Additionally, the integrins a3b1 and a6b4 preferentially bind to laminin-332, which is an important component of the epidermal basement membrane. After the cDNAs for a6 and b4 were cloned, two notable properties were discovered: (1) that the cytoplasmic domain of the b4 subunit is unusually large containing 1000 amino acids, compared to the approximately 50 amino acids of other b subunits and (2) that there are two cytoplasmic variants of the a6 subunit (a6A and a6B), which arise as a result of alternative mRNA splicing. Subsequently, we have determined that the integrin a6b4 is concentrated in hemidesmosomes - junctional complexes that are involved in the attachment of epithelial cells to the extracellular matrix. We have also shown that deletion of the b4 gene (Itgb4) in mice leads to widespread squamous epithelial detachment due to the absence of hemidesmosomes. Importantly, inactivation of the integrin a6b4 in humans has also been associated with loss of hemidesmosomes and fragility of the skin.
The integrin a6b4 and BP180 constitute the two major transmembrane components of hemidesmosomes, while the cytoplasmic constituents include plectin and BP230. By utilizing several different techniques, including transient transfection experiments in immortalized keratinocytes from a b4-deficient patient, we have shown that the three major hemidesmosomal components can bind to the cytoplasmic domain of b4 and that binding of BP180 and plectin to b4 is required for their localization in hemidesmosomes. Furthermore, we have determined that the binding of b4 and F-actin to plectin is mutually exclusive and, in collaboration with Dr. J.M. de Pereda (University of Salamanca-CSIC, Salamanca, Spain), we have mapped the residues that are critical for the interaction with b4 on the crystal structure of the plectin ABD.
A fifth component of hemidesmosomes, the tetraspanin CD151, has been identified and its localization was shown to be dependent on the presence of the a6 subunit. However, its role in these structures is not yet clear. CD151 also forms stable complexes with the integrin a3b1. Both molecules are strongly expressed by podocytes in the kidney. Recently, we have shown that Cd151 null mice develop severe renal failure caused by progressive abnormalities of the glomerular basement membrane and a loss of podocyte foot processes. These abnormalities resemble those seen in mice in which we have conditionally inactivated the integrin a3 subunit in podocytes, and support the existence of a functional a3b1/CD151 complex in vivo. Furthermore, our recent results point to a role of CD151 in adhesion strengthening. Currently, our studies are aimed at understanding all the factors that regulate the formation and the stability of hemidesmosomes and to elucidate the biochemical details of the underlying signaling pathways that are activated by a6b4. Furthermore, we are using conditional knockout mouse lines to study the role of the integrin subunits a3 and b4, as well as CD151, in tumor formation and progression.
Another line of research concerns a novel protein of the outer nuclear envelope, called nesprin-3. We identified it in a yeast-two hybrid screen using the ABD of plectin as bait. We have shown that nesprin-3 recruits plectin to the nuclear envelope, where both proteins are colocalized with keratin intermediate filaments. Nesprin-3 is the first molecule identified that can link the intermediate filaments to the nuclear envelope. Other members of the nesprin family, nesprin-1 and -2, anchor the nucleus to the actin cytoskeleton, and play an important role in nuclear positioning and migration. Further studies have revealed that nesprin-3 interacts with the inner nuclear membrane proteins, SUN1 and SUN2, which in turn can interact with nuclear lamins, thus creating a continuous protein scaffold that physically links the nucleoskeleton to the cytoskeleton. Our current studies focus on understanding the regulation of these interactions during cellular processes, such as cell division and differentiation.
Key publications
De Pereda, J.M., Lillo, M.P., Sonneberg, A. Structural basis of the interaction between integrin alpha6beta4 and plectin at the hemidesmosomes. Embo J. febr. 26 (epub ahead of print) (2009)
Margadant, C., Frijns, E., Wilhelmsen, K., Sonnenberg, A. Regulation of hemidesmosome disassembly by growth factor receptors. Curr. Opin, Cell. Biol. 20-589-598 (2008)
Raymond, K., Kreft, M., Song, J-Y., Janssen, H., Sonnenberg, A. Dual role of alpha4beta6 integrin in epidermal stem cell transformation; tumor suppressive versus tumor-promoting function. Mol. Biol. Cell 18: 4210-4221 (2007)
Wilhelmsen, K. Litjens, S.H., Kuikman, I., Margadant, C., Van Rheen, J., Sonnenberg, A. Serine Phosphorylation of the integrin beta4 subunit is necessary for epidermal growth factor receptor induced hemidesmosome disruption. Mol. Biol. Cell 18: 3512-3522 (2007)
Sachs, N., Kreft, M., Van den Bergh Weerman, M.A., Beynon, A.J., Peters, T.A., Weening, J.J., Sonnenberg, A. Kidney failure in mice lacking the tetraspanin Cd151, J. Cell Biol. 175:33-39 (2006)
Litjens, S.H.M., De Pereda, J.M., Sonnenberg, A. Current insights into the formation and breakdown of hemidesmosomes. Trend Cell. Biol. 16: 376-383 (2006)
Wilhelmsen, K., Litjens, S.H.M., Sonnenberg, A. Multiple functions of the integrin in epiderma alpha6beta4 in epidermal homeostasis and tumorigenesis. Mol. Cell. 26: 2877-2886 (2006)
Wilhelmsen K., Litjens, S.H.M., Kuikman, I., Tshimbalanga, N., Janssen, H., Van der Bout, I., Raymond K., Sonnenberg, A. Nesprin-3, a novel outer nuclear envelope protein, associates wiht the cytoskeletal linker protein plectin. J. Cell Biol. 171:799-810 (2005)
Danen, E.H.J., van Rheenen, J., Franken, W., Huveneers, S., Sonneveld, P., Jalink, K., Sonnenveld, A. Integrin control motile stategy through a Rho-cofilin pathway. J. Cell. Biol. 169: 515-526 (2005)
Koster, J., Van Wilpe, S., Kuikman, I., Litjens, S.H.M., Sonnenberg, A. Role of binding of plectin to the integrin subunit in the assembly of hemidesmosomes. Mol. Biol. Cell 15: 1211-1223 (2004)
Danen, E.H.J., Sonneveld P., Brakebusch, C., Fässler, R., Sonnenberg, A. The fibronectin-binding integrin a5b1 and avb3 differentially modulate RhoA GTP-loading, organization of cell-matrix adhesions and fibronectin fibrillogenesis. J. Cell Biol. 159: 1071-1086 (2002)
Sterk, L.M.Th., Geuijen, C.A.W., Oomen, L.C.J.M., Calafat, J., Janssen, H., and Sonnenberg, A. The tetraspan molecule CD151, a novel constituent of hemidesmosomes, associates with the integrin a6b4 and may regulate the spatial organization of hemidesmosomes. J. Cell Biol. 149: 969-982 (2000)
Gimond, C., van der Flier, A., van Delft, S., Brakebusch, C., Kuikman, I., Collard, J.G., Fässler, R., and Sonnenberg, A. Induction of cell scattering and activation of Rho-like GTPases by expression of b1 integrins in b1-deficient epithelial cells. J. Cell Biol. 147: 1325-1340 (1999)
Geerts, D., Fontao, L., Nievers, M.G., Schaapveld, R.Q.J., Purkis, T., Wheeler, G.N., Lane, E.B., Leigh, I.M., and Sonnenberg, A. Binding of integrin a6b4 to plectin prevents plectin association with F-actin but does not interfere with intermediate filament binding. J. Cell Biol. 147: 417-434 (1999)
Gimond, C., Baudoin, C., van der Neut, R., Kramer, D., Calafat, J., and Sonnenberg, A.
Cre-loxP-mediated inactivation of the a6A integrin splice variant in vivo: evidence for a
specific functional role of a6A in lymphocyte migration but not in early heart
development. J. Cell Biol.143: 253-266 (1998)
Schaapveld, R.Q.J., Borradori, L., Geerts, D., van Leusden, M.R., Kuikman, I., Nievers, M.G., Steenbergen, R.D.M., Snijders, P.J.F., and Sonnenberg, A. Hemidesmosome formation is initiated by the b4 integrin subunit, requires complex formation of b4 and HD1/plectin and involves a direct interaction between b4 and BP180. J. Cell Biol. 142: 271-284 (1998)
Borradori, L., Koch, P.J., Niessen, C.M., Erkeland, S., van Leusden, M.R., and Sonnenberg, A. The localization of bullous pemphigoid antigen 180 (BP180) in hemidesmosomes is mediated by its cytoplasmic domain and seems to be regulated by the b4 integrin subunit. J. Cell Biol. 136: 1333-1347 (1997)
Van der Neut, R., Krimpenfort, P., Calafat, J., Niessen, C.M., and Sonnenberg A. Epithelial detachment due to absence of hemidesmosomes in integrin b4 null mice. Nature Genet. 13: 366-369 (1996)
Reviews
Wilhelmsen, K., Litjens, S.H.M., and Sonnenberg, A. Multiple functions of the integrin a6b4 in epidermal homeostasis and tumorigenesis. Mol. Cell. Biol. 26: 2877-2886 (2006).
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).
Wilhelmsen, K., Ketema, M., Truong, H., and Sonnenberg, A. (2006) KASH-domain proteins in nuclear migration, anchorage an d other process. J. Cell Sci., in press
More publication by Arnoud Sonnenberg on PubMed
Biographic sketch
Arnoud Sonnenberg was trained in several laboratories, including the Salk Institute and the Scripps Clinic and Research Foundation, before obtaining his PhD from the University of Amsterdam in 1990. Subsequently, he joined the Division of Cell Biology at the Netherlands Cancer Institute in Amsterdam, where he became head of the Division in 2003. He currently directs a research group of 9 people and works as an editor of the J. Cell Science.
Coworkers
Ports, M. PhD Postdoc
Postel, R. PhD Postdoc
Rifes, P. PhD Postdoc
Secades, P. PhD Postdoc
Frijns, E. MSc Graduate student
De Groot, D.J. MSc Graduate student
Ketema M. MSc Graduate student
Margadant, C. MSc Graduate student
Sachs, N. MSc Graduate student
Kreft, M MSc Technical Staff
Kuikman, I. MSc Technical Staff
Position available
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