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The Den Hertog group studies the function of protein-tyrosine phosphatases in development and disease, using biochemical and cell biological approaches.
Protein phosphorylation on tyrosine residues is an important cell signaling mechanism that has a pivotal role in many biological processes, including cell proliferation, migration and transformation. Cellular protein phosphotyrosine levels are regulated by the antagonistic activities of the protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs).
We are interested in the function of PTPs in development and disease. Using biochemical and cell biological approaches, we study PTP-signaling in order to obtain insight into conceptual questions about substrates, regulation, ligands and effectors. Over the years, we established that the proto-typical RPTPalpha is regulated by dimerization, oxidation and phosphorylation.
We use the zebrafish to elucidate the role of PTPs and PTKs in early vertebrate development. We found that PTKs Fyn and Yes have an important role in convergence and extension cell movements in zebrafish gastrulation. These PTKs signal in parallel to non-canonical Wnts, upstream of the small GTPase RhoA. Moreover, we found that the PTP Shp2 is essential for normal convergence and extension cell movements. Expression of Shp2 variants with mutations that were identified in human Noonan or LEOPARD syndrome induced phenotypes that were reminiscent of the symptoms in human patients with these syndromes, including cardiac and craniofacial defects.
PTEN is a tumor suppressor gene that belongs to the PTP superfamily and exhibits lipid phosphatase activity with high selectivity for the 3-position of phosphatidylinositol(3,4,5)trisphosphate. The zebrafish genome encodes two PTEN genes: ptena and ptenb. We isolated null mutants of both PTEN genes and found that adult zebrafish with a single wild type PTEN allele develop hemangiosarcomas, blood-filled clusters of blood vessels with endothelial origin. Double homozygous ptena-/-ptenb-/- mutant embryos are embryonic lethal and display a pleiotropic phenotype, including hyperproliferation of endothelial cells, resulting in hyperbranching of blood vessels. Hematopoiesis is also affected in ptena-/-ptenb-/- mutants. Hematopoietic stem and progenitor cells (HSPCs) hyperproliferate and arrest during differentiation in embryos lacking functional PTEN, resulting in enhanced numbers of blood cell progenitors, but no mature blood cells.
We and others have shown that PTPs are tightly regulated by oxidation. Zebrafish have the capacity to regenerate organs and body parts. Amputation of the caudal fin leads to rapid, transient production of reactive oxygen species, which is required for epimorphic regeneration. Recently, we demonstrated that PTPs are differentially oxidized in response to caudal fin amputation. Moreover, there is a differential requirement for PTPs during regeneration, in that mutant zebrafish embryos lacking Shp2 or pten do not regenerate, whereas RPTPalpha is dispensable for regeneration.
In parallel to the research line above, a second line of research was developed in the den Hertog lab over the years, aimed at identification of biologically active molecules. Due to an ageing world population, globalization and drug resistance, there is a constant need for new and more effective drugs. The number of drugs that are being used in the clinic is limited and the number of biologically active molecules in these drugs is only ~1,500. The goal of this project is to identify novel chemical scaffolds with biological activity that may provide the starting point for the development of new drugs. Fungi are well-known for the production of a wide variety of secondary metabolites with biological activity. Commonly used drugs, including penicillin, cyclosporin and lovastatin all originate from fungi. Continuous discovery of novel compounds from fungi proves that the fungal kingdom as a source of new compounds is far from depleted. We have generated a library of crude growth media from >10,000 fungal species in collaboration with the Westerdijk Fungal Biodiversity Institute. These growth media contain the secreted secondary metabolites from these fungi. We have assessed biological activity of these fungal filtrates using zebrafish embryogenesis as read-out. Following incubation from 6 hpf onwards, 1,535 fungal secondary metabolites induced morphological abnormalities at 2 dpf, varying from an undulating notochord to pigmentation, heart and tail defects, amongst others. Fungal strains were selected based on the phenotype they induced and in collaboration with the chemistry department at Utrecht University, we have set up a pipeline to identify bioactive compounds by activity-guided purification using HPLC. Purified active compounds were identified using LCMS, UV-Vis spectrometry, high resolution mass spectrometry and NMR. We have established the biological activity in zebrafish of more than 60 known fungal metabolites and we identified several bioactive metabolites that have not been described before.
Hoeksma J, Misset T, Wever C, Kemmink J, Kruijtzer J, Versluis K, Liskamp RMJ, Boons GJ, Heck AJR, Boekhout T, den Hertog J
Download|2019
Wu W, Hale AJ, Lemeer S, den Hertog J
Download|2017
Choorapoikayil S, Kers R, Herbomel P, Kissa K and den Hertog J
Download|2014
Bonetti M, Paardekooper Overman J, Tessadori F, Noël E, Bakkers J and den Hertog J
Jopling C, van Geemen D, den Hertog J
Download|2007
Blanchetot C, Tertoolen LGJ, den Hertog J
Download|2002
Bobone S, Pannone L, Biondi B, Solman M, Flex E, Canale VC, Calligari P, De Faveri C, Gandini T, Quercioli A, Torini G, Venditti M, Lauri A, Fasano G, Hoeksma J, Santucci V, Cattani G, Bocedi A, Carpentieri G, Tirelli V, Sanchez M, Peggion C, Formaggio F, den Hertog J, Martinelli S, Bocchinfuso G, Tartaglia M, Stella L.
Download|2021
Ouyang X, Hoeksma J, van der Velden G, Beenker WAG, van Triest MH, Burgering BMT, den Hertog J
Leijten NM, Bakker P, Spaink HP, den Hertog J, Lemeer S
Blokzijl-Franke S, Ponsioen B, Schulte-Merker S, Herbomel P, Kissa K, Choorapoikayil S, den Hertog J
Hoeksma J, van der Zon GCM, Ten Dijke P, den Hertog J
Download|2020
Cohen-Sharir Y, Kuperman Y, Apelblat D, den Hertog J, Spiegel I, Knobler H, Elson A
Ferese R, Bonetti M, Consoli F, Guida V, Sarkozy A, Lepri FR, Versacci P, Gambardella S, Calcagni G, Margiotti K, Sparascio FP, Hozhabri H, Mazza T, Digilio MC, Dallapiccola B, Tartaglia M, Marino B, den Hertog J, De Luca A
Download|2018
Hale AJ, den Hertog J
Download|20180501
Hale AJ, Kiai A, Sikkens J, den Hertog J
Download|20170501
Ciarlo C, Kaufman CK, Michael J, D’Amato C, Kinikoglu B, Yang S, Blokzijl-Franke S, den Hertog J, Schlaeger T, Zhou Y, Liao EC, Zon LI
Download|20170504
den Hertog J, van Oudenaarden A
den Hertog J, de Laat SW
Hale AJ, ter Steege E, den Hertog J
den Hertog J
Download|20160501
Blokhuis AM, Koppers M, Groen EJN, Dini Modigliani S, van den Heuvel DMA, Anink JJ, Fumoto K, van Diggelen F, Snelting A, Sodaar P, Demmers JAA, Veldink JH, Aronica E, Bozzoni I, den Hertog J, van den Berg LH, Pasterkamp RJ
Stumpf M, Blokzijl-Franke S, den Hertog J
Blokhuis AM, Koppers M, Groen EJN, Dini Modigliani S, van den Heuvel DMA, ... den Hertog J, van den Berg LH, Pasterkamp RJ
20160501
Stumpf M, den Hertog J
Stanford SM, Svensson MN, Sacchetti C, Pilo CA, Wu DJ, Kiosses WB, ... den Hertog J, Elson A, Sap J, Mydel P, Boyle DL, Corr M, Firestein GS, Bottini N.
Stumpf M, Choorapoikayil S and den Hertog J
Download|20150501
Vissers LELM, Bonetti M, Paardekooper Overman J, Nillesen WM ... Tartaglia M, van der Burgt I, Yntema HG and den Hertog J
Paardekooper Overman J, Preisinger C, Prummel K, Bonetti M, Giansanti P, Heck A and den Hertog J
Download|20140501
Pulido R, Baker SJ, Barata JT, Carracedo A, Cid VJ, Chin-Sang ID, Davé V, den Hertog J ... Woscholski R, Wu H, Leslie NR
Paardekooper Overman J, Yi JS, Bonetti M, Soulsby M, Preisinger C, Stokes MP, Hui L, Silva JC, Overvoorde J, Giansanti P, Heck AJR, Kontaridis MI, den Hertog J and Bennett AM
Leslie NR and den Hertog J
Finkelshtein E, Lotinun S, Levy-Apter E, Arman E, den Hertog J, Baron R and Elson A
Bonetti M, Rodriguez-Martinez V, Paardekooper Overman J, Overvoorde J, van Eekelen M, Jopling C and den Hertog J
Albers HMHG, Kuijl C, Bakker J, Hendrickx L, Wekker S, Farhou N, Liu N, Blasco-Moreno B, Scanu T, den Hertog J, Celie P, Ovaa H and Neefjes J
van Ameijde J, Overvoorde J, Knapp S, den Hertog J, Ruijtenbeek R, Liskamp RM
Paardekooper Overman J and den Hertog J
Download|
Noël ES, Verhoeven M, Lagendijk AK, Tessadori F, Smith K, Choorapoikayil S, den Hertog J, Bakkers J
Download|20130501
Choorapoikayil S, Weijts B, Kers R, de Bruin A, den Hertog J
Choorapoikayil S, Overvoorde J, den Hertog J
Hendriks WJ, Elson A, Harroch S, Pulido R, Stoker A, den Hertog J
Böhmer F, Szedlacsek S, Tabernero L, Ostman A, den Hertog J (
Kanwal Z, Zakrzewska A, den Hertog J, Spaink HP, Schaaf MJM, Meijer AH
Guida V, Ferese R, Rocchetti M, Bonetti M, Sarkozy A, Cecchetti S, Gelmetti V, Lepri F, Copetti M, Lamorte G, Digilio MC, Marino B, Zaza A, den Hertog J, Dallapiccola B, De Luca A
Ferreira PA, Ruela-de-Sousa RR, Queiroz KC, Souza AC, Milani R, Pilli RA, Peppelenbosch MP, den Hertog J, Ferreira CV
Download|20120501
van Eekelen M, Runtuwene V, Masselink W, den Hertog J
Choorapoikayil S, Kuiper RV, de Bruin A, den Hertog J
Gutierrez A, Grebliunaite R, Feng H, Kozakewich E, Zhu S, Guo F, Payne E, Mansour M, Dahlberg SE, Neuberg DS, den Hertog J, Prochownik EV, Testa JR, Harris M, Kanki JP, Look AT
Download|20110501
Runtuwene V, van Eekelen M, Overvoorde J, Rehmann H, Yntema HG, Nillesen WM, van Haeringen A, van der Burgt I, Burgering B, den Hertog J
van Eekelen M, Overvoorde J, van Rooijen C and den Hertog J
Download|20100501
Vacaru AM, den Hertog J
van Eekelen M, Runtuwene V, Overvoorde J, den Hertog J
Vacaru, A.M. and den Hertog, J.
Boersema PJ, Foong LY, Ding VM, Lemeer S, van Breukelen B, Philp R, Boekhorst J, Snel B, den Hertog J, Choo AB, Heck AJ
Download|20090501
den Hertog J, van Eekelen M
20090501
Rodriguez, F., Vacaru, A., Overvoorde, J. and den Hertog, J.
Download|20080501
Lemeer, S., Jopling, C., Gouw, J., Mohammed, S., Heck, A.J.R., Slijper, M. and den Hertog, J.
Bodrikov, V., Sytnyk, V., Leshchyns’ka, I., den Hertog, J. and Schachner, M.
Cid, V.J., Rodrıguez-Escudero, I., Andres-Pons, A., Roma-Mateo, C., Gil, A., den Hertog, J., Molina, M. and Pulido, R.
Groen, A., Overvoorde, J., van der Wijk, T. and den Hertog, J.
Bispo de Jesus, M, Zambuzzi, W.F., Ruela de Sousa, R.R., Areche, C. ... den Hertog, J., de Paula, E., Ferreira, C.V.
Lemeer, S., Pinkse, M.W.H., Mohammed, S., van Breukelen, B., den Hertog, J. Slijper, M. and Heck, A.J.R.
20080501
den Hertog, J. Östman, A and Böhmer, F.-D.
Faucherre, A., Taylor, G.S., Overvoorde, J., Dixon, J.E. and den Hertog, J.
Jopling, C., van Geemen, D. and den Hertog, J.
Download|20070501
Lemeer, S.M., Ruijtenbeek, R., Pinkse, M.W.H., Jopling, C., Heck, A.J.R., den Hertog, J. and Slijper, M.
Lemeer, S., Jopling, C., Naji, F., Ruijtenbeek, R., Slijper, M., Heck, A.J.R. and den Hertog, J.
Knöll, R., Postel, R., Wang, J., Krätzner, R., Hennecke, G., Vacaru, A.M. ... Den Hertog, J., van Eeden, F.J.M., Peters, P.J., Hasenfuss, G., Chien, K.R.and Bakkers, J.
Jopling, C. and den Hertog, J.
Yang, J., Groen, A., Lemeer, S., Jans, A., Slijper, M., Roe, S.M., den Hertog, J. and Barford, D.
Diks, S.H., Bink, R.J., van de Water, S., Joore, J., van Rooijen, C., Verbeek, F.J., den Hertog, J., Peppelenbosch, M.P., Zivkovic, D.
Download|20060501
Mitola, S., Brenchio, B., Piccinini, M., Tertoolen, L., Zammataro, L., Breier, G., Rinaudo, M.T., den Hertog, J. and Bussolino, F.
Hsia, D.A., Lim, S.T., Bernard-Triflo, J.A., Mitra, S.K., Tanaka, S., den Hertog, J., Streblow, D.N., Ilic, D., Ginsberg, M.H. and Schlaepfer, D.D.
Download|20050501
De Guzman, B., Hisatsune, J., Nakayama, M., Yahiro, K., Wada, A., Yamasaki, E., Nishi, Y., Yamazaki, S., Azuma, T., Ito, Y., Ohtani, M., van der Wijk, T., den Hertog, J., Moss, J. and Hirayama, T.
den Hertog, J
20050501
Groen, A., Lemeer, S., van der Wijk, T., Overvoorde, J., Heck, A.J.R., Ostman, A., Barford, D., Slijper, M., and den Hertog, J.
den Hertog, J., Groen, A. and van der Wijk, T.
Bodrikov, V., Leshchyns’ka, I, Sytnyk, V., Overvoorde, J., den Hertog, J. and Schachner, M.
van der Wijk, T., Blanchetot, C. and den Hertog, J
Lorber, B., Berry, M., Hendriks, W., den Hertog, J., Pulido, R. and Logan, A.
Download|20040501
van der Wijk, T., Overvoorde, J. and den Hertog, J.
Persson, C., Sjöblom, T., Groen, A., Kappert, K., Engström, U., Hellman, U., Heldin, C.H., den Hertog, J. and Östman, A.
den Hertog, J.
20040501
Download|20030501
van der Wijk, T., Blanchetot, C., Overvoorde, J. and den Hertog, J.
20030501
Toledano-Katchalski, H., Tiran, Z., Sines, T., Shani, G., Granot-Attas, S., den Hertog, J. and Elson, A.
Bink, R.J., Habuchi, H., Lele, Z., Dolk, E., Joore, J., Rauch, G.J., Geisler, R., Wilson, S., den Hertog, J., Kimata, K. and Zivkovic, D.
den Hertog, J., van der Wijk, T., Tertoolen, L.G.J. and Blanchetot, C.
Blanchetot, C., Tertoolen, L.G., and den Hertog, J.
Download|20020501
van der Sar, A., Zivkovic, D., and den Hertog, J.
Blanchetot, C., Tertoolen, L.G., Overvoorde, J. and den Hertog, J.
Gross, S., Blanchetot, C., Schepens, J., Albet, S., Lammers, R., den Hertog, J. and Hendriks, W.
Rohn, J.L., Zhang, Y.H., Aalbers, R.I.J.M., Otto, N., den Hertog, J., Henriquez, N.V., van de Velde, C.J.H., Kuppen, P.J.K., Mumberg, D., Donner, P. and Noteborn, M.H.M.
Tertoolen, L.G., Blanchetot, C., Jiang, G., Overvoorde, J., Gadella, T.W.J., Hunter, T., and den Hertog, J.
Download|20010501
van der Sar, A., Betist, M., de Fockert, J., Overvoorde, J., Zivkovic, D., and den Hertog, J.
Blanchetot, C. and den Hertog, J.
Download|20000501
Buist, A., Blanchetot, C., and den Hertog, J.
Buist, A., Blanchetot, C., Tertoolen, L.G., and den Hertog, J.
Jiang, G., den Hertog, J., and Hunter, T.
Buist, A., Zhang, Y.L., Keng, Y.F., Wu, L., Zhang, Z.Y., and den Hertog, J.
Download|19990501
de Laat, S.W., Boonstra, J., Defize, L.H., Kruijer, W., van der Saag, P.T., Tertoolen, L.G., van Zoelen, E.J., and den Hertog, J
den Hertog, J., Blanchetot, C., Buist, A., Overvoorde, J., van der Sar, A., and Tertoolen, L.G.
Jiang, G., den Hertog, J., Su, J., Noel, J., Sap, J., and Hunter, T.
Kester, H.A., Blanchetot, C., den Hertog, J., van der Saag, P.T., and van der Burg, B.
van der Sar, A.M., de Fockert, J., Betist, M., Zivkovic, D., and den Hertog, J.
Verheijen, M.H., Wolthuis, R.M., Defize, L.H., den Hertog, J., and Bos, J.L.
Buist, A., Tertoolen, L.G., and den Hertog, J.
Download|19980501
van Puijenbroek, A.A., van Weering, D.H., van den Brink, C.E., Bos, J.L., van der Saag, P.T., de Laat, S.W., and den Hertog, J
Download|19970501
Wu, L., Buist, A., den Hertog, J., and Zhang, Z.Y.
Ameerun, R.F., de Winter, J.P., van den Eijnden-van Raaij, A.J., den Hertog, J., de Laat, S.W., and Tertoolen, L.G.
Download|19960501
Bilwes, A.M., den Hertog, J., Hunter, T., and Noel, J.P.
den Hertog, J. and Hunter, T.
den Hertog, J., Overvoorde, J., and de Laat, S.W.
19960501
Chen, L., Wu, L., Otaka, A., Smyth, M.S., Roller, P.P., Burke, T.R.J., den Hertog, J., and Zhang, Z.Y.
Download|19950501
den Hertog, J., Sap, J., Pals, C.E., Schlessinger, J., and Kruijer, W.
den Hertog, J., Tracy, S., and Hunter, T.
Download|19940501
den Hertog, J. and Kruijer, W.
de Groot, R.P., den Hertog, J., Vandenheede, J.R., Goris, J., and Sassone-Corsi, P.
Download|19930501
den Hertog J, Pals CEGM, Peppelenbosch MP, Tertoolen LGJ, de Laat SW, Kruijer W
Download|19931104
den Hertog, J., Pals, C.E., Peppelenbosch, M.P., Tertoolen, L.G., de Laat, S.W., and Kruijer, W.
de Laat, S.W., de Groot, R.P., den Hertog, J., Rijken, P.J., Verkleij, A.J., Kruijer, W., and Boonstra, J.
19920501
den Hertog, J., de Groot, R.P., de Laat, S.W., and Kruijer, W.
Download|19920501
den Hertog, J., Pals, C.E., Jonk, L.J., and Kruijer, W.
Peppelenbosch, M.P., Tertoolen, L.G., den Hertog, J., and de Laat, S.W.
de Groot, R.P., Rijken, P.J., den Hertog, J., Boonstra, J., Verkleij, A.J., de Laat, S.W., and Kruijer, W.
Download|19910501
den Hertog, J., de Laat, S.W., Schlessinger, J., and Kruijer, W.
den Hertog, J., Eman, R., Tertoolen, L.G., de Laat, S.W., and Kruijer, W.
19910501
Shen, S., Kruyt, F.A., den Hertog, J., van der Saag, P.T., and Kruijer, W.
Jeroen den Hertog is group leader and managing director at the Hubrecht Institute and professor of Molecular Developmental Zoology at Leiden University. The Den Hertog group uses the zebrafish as a model system. They investigate the function of protein-tyrosine phosphatases (PTPs). PTP-signaling has an important role in many biological processes, including cell proliferation, migration and transformation. The Den Hertog group studies the regulation, substrates, ligands and effectors in PTP-signaling using biochemical, molecular and cell biological, and genetic approaches during zebrafish development and regeneration of the caudal fin.
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