Structure and Function of Collagen Receptor Integrins
>Current research in biochemistry
Contact information
Jyrki Heino
jyrki.heino[at]utu.fi
Members
Professor Jyrki Heino, M.D., Ph.D.
Senior Scientist Jarmo Käpylä, Ph.D., Docent
Post-docs Pekka Rappu, Ph.D. / Eeva Rissanen, Ph.D. / Johanna Jokinen, Ph.D.
Ph. D. students Pasi Kankaanpää, M.Sc. / Maria Salmela, M.Sc. / Camilla Nylund M.Sc. / Anna-Brita Puranen, M.Sc. / Matti Lahti, M.Sc. / Kalle Sipilä, M.Sc.
Technician Maria Tuominen
Background
The integrin family of cell adhesion receptors is composed of 24 heterodimeric receptors. Four integrins, alpha1beta1, alpha2beta1, alpha10beta1 and alpha11beta1, form a structurally and functionally separate subgroup of the collagen receptors. Despite the fact that collagens are found in all metazoans, integrin-type collagen receptors seem to have evolved quite late, and they have been found in vertebrates only. Collagen receptor integrins participate in the regulation of mesenchymal stem cell proliferation, platelet function, angiogenesis, immunoresponse and extracellular matrix turnover. In addition, they seem to be important for the pathogenesis of many human diseases, such as cancer, thrombosis and inflammatory diseases.
Research
Our research group is studying the structure-function relationship of the collagen receptor integrins. The most important methods used include the production of recombinant protein domains, functional assays and mutations of the domains, bioinformatics as well as the expression and analysis of the full-length receptor proteins on cell surface. In addition to the structural work we are studying integrin function during signal transduction, lateral movement on cell surface and internalization. In these experiments we use the general methods of molecular cell biology, imaging by confocal microscopy and proteomics (iTRAQ and SILAC). A separate project is aimed to the development of new computer programs for the analysis of data from confocal microscopy (BioImageXD).
We are presently the only laboratory that has produced the ligand binding alphaI domains of all four collagen receptors as recombinant proteins and systematically compared their ligand binding properties. We are studying the structural details of the recognition of different collagen subtypes. This has lead to a project aimed at development of small molecular inhibitors for collagen receptors.
From left to right: Kalle Sipilä, Matti Lahti, Mari Salmela, Jarmo Käpylä, Jyrki Heino, Johanna Jokinen, Henri Niskanen, Maria Tuominen and Pekka Rappu.
Significance
In our published papers we have described the opposite roles of alpha1beta1 and alpha2beta1 integrins in the regulation of matrix turnover, the first alpha2beta1 integrin specific signaling pathways and selective recognition of collagen subtypes by all four collagen receptors. We have recently shown that cells can use collagen receptors in direct and indirect binding to collagen fibrils. We have also discovered that alpha2beta1 integrin guides human echovirus-1 into a unique entry pathway, which has led to further studies showing the essential role of receptor clustering in the subsequent targeting of the virus and its receptor. During the past years we have also studied integrin functions in wound healing, cancer invasion and fibrosis.
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Recent publications
Hellman M., Tossavainen H., Rappu P., Heino J., Permi P. (2011) Characterization of Intrinsically Disordered Prostate Associated Gene (PAGE5) at Single Residue Resolution by NMR Spectroscopy. PLoS One 6(11):e26633
Lahti M., Bligt E., Niskanen H., Parkash V., Brandt A.M., Jokinen J., Patrikainen P., Käpylä J., Heino J., Salminen T.A. (2011) Structure of Collagen Receptor Integrin ?1I Domain Carrying the Activating Mutation E317A. J. Biol. Chem. 286:43343-51.
Chouhan B., Denesyuk A., Heino J., Johnson M.S., Denessiouk K. (2011) Conservation of the human integrin-type Beta-propeller domain in bacteria. PLoS One 6(10):e25069
Koivunen J.T., Nissinen L., Käpylä J., Jokinen J., Pihlavisto M., Marjamäki A., Heino J., Huuskonen J., Pentikäinen O.T. (2011) Fluorescent small molecule probe to modulate and explore ?2?1 integrin function. J. Am. Chem. Soc. 133(37):14558-61.
Ivaska J, Heino J. (2011) Cooperation between integrins and growth factor receptors in signaling and endocytosis. Annu. Rev. Cell Dev. Biol. 27:291-320.
Larjava H, Koivisto L, Häkkinen L, Heino J. (2011) Epithelial integrins with special reference to oral epithelia. J. Dent. Res. 2011 90(12):1367-76.
Larjava H, Wiebe C, Gallant-Behm C, Hart DA, Heino J, Häkkinen L. (2011) Exploring scarless healing of oral soft tissues. J. Can. Dent .Assoc. 77:b18.
Veit G., Zwolanek D., Eckes B., Niland S., Käpylä J., Zweers M.C., Ishada-Yamamoto A., Krieg T., Heino J., Eble J.A., Koch M. (2011).Collagen XXIII, Novel Ligand for Integrin alpha2beta1 in the Epidermis. J. Biol. Chem. 286(31):27804-27813
Rappu P., Nylund C., Ristiniemi N., Kulpakko J., Vihinen P., Hernberg M., Mirtti T., Alanen K., Kallajoki M., Vuoristo M. S., Pyrhönen S., Heino J. (2011) Detection of melanoma-derived cancer-testis antigen CT16 in patient sera by a novel immunoassay. Int. J. Cancer 128(10): 2382-2392
Zeltz, C.; Brézillon, S.; Käpylä, J.; Eble, J.A.; Bobichon, H.; Terryn, C.; Perreau, C.; Franz, C.M.; Heino, J.; Maquart, F.X. & Wegrowski, Y. 2010: Lumican inhibits cell migration through alpha2beta1 integrin. Experimental Cell Research 316(17): 2922-2931.
Ivaska, J. and J. Heino. (2010) Interplay between cell adhesion and growth factor receptors: from the plasma membrane to the endosomes. Cell Tissue Res. 339:111-120.
Jokinen, J., D. J. White, M. Salmela, M. Huhtala, J. Kapyla, K. Sipila, J. S. Puranen, L. Nissinen, P. Kankaanpaa, V. Marjomaki, T. Hyypia, M. S. Johnson, and J. Heino. (2010) Molecular mechanism of alpha2beta1 integrin interaction with human echovirus 1. EMBO J. 29:196-208.
Nissinen, L., O. T. Pentikainen, A. Jouppila, J. Kapyla, M. Ojala, J. Nieminen, A. Lipsanen, H. Lappalainen, B. Eckes, M. S. Johnson, R. Lassila, A. Marjamaki, and J. Heino. (2010) A small-molecule inhibitor of integrin alpha2 beta1 introduces a new strategy for antithrombotic therapy. Thromb. Haemost. 103:387-397.
Heino, J., M. Huhtala, J. Kapyla, and M. S. Johnson. (2009) Evolution of collagen-based adhesion systems. Int. J. Biochem. Cell Biol. 41:341-348.
Heino, J. and J. Kapyla. (2009) Cellular receptors of extracellular matrix molecules. Curr. Pharm. Des. 15:1309-1317.
Johnson, M. S., N. Lu, K. Denessiouk, J. Heino, and D. Gullberg. (2009) Integrins during evolution: evolutionary trees and model organisms. Biochim. Biophys. Acta 1788:779-789.
Abair, T. D., M. Sundaramoorthy, D. Chen, J. Heino, J. Ivaska, B. G. Hudson, C. R. Sanders, A. Pozzi, and R. Zent. (2008) Cross-talk between integrins alpha1beta1 and alpha2beta1 in renal epithelial cells. Exp. Cell Res. 314:3593-3604.
Karjalainen, M., E. Kakkonen, P. Upla, H. Paloranta, P. Kankaanpaa, P. Liberali, G. H. Renkema, T. Hyypia, J. Heino, and V. Marjomaki. (2008) A Raft-derived, Pak1-regulated entry participates in alpha2beta1 integrin-dependent sorting to caveosomes. Mol. Biol. Cell 19:2857-2869.
Tulla, M., J. Helenius, J. Jokinen, A. Taubenberger, D. J. Muller, and J. Heino. (2008) TPA primes alpha2beta1 integrins for cell adhesion. FEBS Lett. 582:3520-3524.
Tulla, M., M. Lahti, J. S. Puranen, A. M. Brandt, J. Kapyla, A. Domogatskaya, T. A. Salminen, K. Tryggvason, M. S. Johnson, and J. Heino. (2008) Effects of conformational activation of integrin alpha 1I and alpha 2I domains on selective recognition of laminin and collagen subtypes. Exp. Cell Res. 314:1734-1743.
Upla, P., V. Marjomaki, L. Nissinen, C. Nylund, M. Waris, T. Hyypia, and J. Heino. (2008) Calpain 1 and 2 are required for RNA replication of echovirus 1. J. Virol. 82:1581-1590.
Vuoriluoto, K., J. Jokinen, K. Kallio, M. Salmivirta, J. Heino, and J. Ivaska. (2008) Syndecan-1 supports integrin alpha2beta1-mediated adhesion to collagen. Exp. Cell Res. 314:3369-3381.
>Current research in biochemistry