Bos Group

Recent and selected publications

Post A, Pannekoek WJ, Ponsioen B, Vliem MJ, Bos JL.

Rap1 spatially controls ArhGAP29 to inhibit Rho signaling during endothelial barrier regulation.
Mol Cell Biol. 2015 May 11. pii: MCB.01453-14. [Epub ahead of print]

A follow-up on the 2013 PNAS paper, now showing that Radil is responsible for the translocation of ArhGAP29 to the plasma membrane, but the trimeric complex Rasip1-Radil-ArhGAP29 is required for biologic function


Bruurs L.J., Bos J.L.

Mechanisms of isoform specific Rap2 signaling during enterocytic brush border formation.
PLoS One. 2014 Sep 9;9:e106687


Consonni S.V., Brouwer P.M., van Slobbe E.S, and Bos J.L. The PDZ domain of the guanine nucleotide exchange factor PDZGEF directs binding to phosphatidic acid during brush border formation. PLoS One, 2014, 9, e98253


Consonni, S.V., Maurice, M.M. and Bos J.L. DEP domains: structurally similar, but functionally different. Nature Rev. Mol. Cell. Biol. 2014, 15, 357-363

Review dedicated to Tony Pawson on the versatile function of DEP domains


Post A., Pannekoek, W.-J., Ross, S.H., Verlaan, I., Brouwer, P.M. and Bos, J.L. Rasip1 mediates Rap1 regulation of Rho in endothelial barrier function through ArhGAP29. Proc. Natl. Acad. Sci. 2013, 110, 11427-11432 

This paper of describes for the first time a clear connection between Rap1 and Rho signalling in the control of cell spreading and endothelial barrier function.


Gloerich M., Ten Klooster J.P., Vliem M.J., Koorman T., Zwartkruis F.J., Clevers H.,

Bos JL. Rap2A links intestinal cell polarity to brush border formation.

Nat Cell Biol. 2012 , 14, 793-801. (PDF Article)

This beautiful paper of Martijn Gloerich describes the pathway form polarity to brush border formation: Apical PIP2 recruits PLD to produce apical PA which serves as a landmark for the RapGEF, PDZ-GEF. This GEF activates Rap2A followed by the recrutement of the kinase TNIK, and subsequently the kinase Mst4, resulting in the phosphorylation of Ezrin and brush border formation.  


Bos JL, Pannekoek WJ. Semaphorin signaling meets rap.

Sci Signal. 2012 Feb 21;5(212). (PDF Article)


Consonni SV, Gloerich M, Spanjaard E, Bos JL. cAMP regulates DEP-domain-mediated binding of the guanine nucleotide exchange factor Epac1 to phosphatidic acid at the plasma membrane. Proc. Natl. Acad. Sci. 2012, 109, 3814-3819. (PDF Article)

Paper describes the mechanism of Epac translocates to the plasma membrane upon cAMP stimulation. A conformational change in the DEP domain induced by cAMP binding results in a binding site for PA. 


Pannekoek WJ, van Dijk J, Chan OY, Huveneers S, Linnemann J, Spanjaard E, Brouwer P, van der Meer AJ, Zwartkruis GJ, Rehmann H,  de Rooij J, Bos JL. Epac1 and PDZ-GEF cooperate in Rap1 mediated endothelial junction control. Cell. Signal., 2011, 23, 2056-2064. (PDF Article)

Paper describes the important role of the Rap1GEF PDZ-GEF in barrier function of endothelial cells, in addition to the modulatory role of the cAMP regulated RapGEF, Epac1


Gloerich M, Bos JL. Regulating Rap small G-proteins in time and space. Trends in Cell Biol. 2011, 21, 615-623. (PDF Article)


Gloerich M, Vliem MJ, Prummel E, Meijer LAT, Rensen MGA, Rehmann H, Bos JL. The nucleoporin RanBP2 tethers the cAMP effector Epac1 resulting in the inhibition of Epac1 catalytic activity. J. Cell Biol. 2011, 193:1009-1020.

Paper describes the binding of Epac1 to the Zn-fingers of RapBP2 resulting in a localisation at the nuclear pore. This interaction results in the inactivation of Epac1. Epac1 is released during mitosis due to phosphorylation of RanBP2 suggesting a role of Epac1 during mitosis.


Ross SH, Post A, Raaijmakers JH, Verlaan I, Gloerich M, Bos JL. Ezrin is required for efficient Rap1-induced spreading. J. Cell Sci. 2011, 124:1808-1818.

Paper describes the use of a limited genetic screen to identify the essential role of Erzin and the Rap effector Radil in Rap1-induced cell spreading, but not cell adhesion, also revealing that these two processes are differentially regulated by Rap1. 


Gloerich M, Ponsioen B, Vliem MJ, Zhang Z, Zhao J, Kooistra MR, Price LS, Ritsma L, Zwartkruis FJ, Rehmann H, Jalink K, Bos JL. Spatial regulation of cAMP-Epac1 signaling in cell adhesion by ERM proteins. Mol Cell Biol. 2010, 30:5421-5431.

Paper describes the translocation of Epac1 by thrombin-Rho-mediated signalling to polarised positions in the cell where active ezrin, radixin or moesin serve as anchors 


Gloerich M, Bos JL. Epac: Defining a new mechanism for cAMP action. Annu. Rev.Pharmacol. Toxicol. 2010, 50:355-375. (PDF Article) 

Recent Review.


Ponsioen B, Gloerich M, Ritsma L, Rehmann H, Bos JL, Jalink K. Direct spatial control of Epac1 by cAMP. Mol. Cell. Biol. 2009, 29:2521-2531. (PDF Article)

Paper describes the translocation of Epac1 to the plasma membrane through direct binding of cAMP. This in addition to the previously described allosteric activation of Epac1 by cAMP. 


Van Dam TJ, Rehmann H, Bos JL, Snel B. Phylogeny of the CDC25 homology domain reveals rapid differentation of Ras pathways between early animals and fungi. Cell Signal. 2009, 21:1579-1585. (PDF Article)

Paper describes the evolution of guanine nucleotide exchange factors for Ras proteins.


Raaijmakers JH and Bos JL. Specificity inRas and Rap signaling. J.Biol.Chem. 2009, 284:10955. Review (PDF Article)


Pannekoek WJ, Kooistra MR, Zwartkruis FJ, Bos JL. Cell-cell junction formation: The role of Rap1 and Rap1 guanine nucleotide exchange factors. Biochem.Biophys.Acta 2009, 1788:790-796. Review. (PDF Article)


Vliem MJ, Ponsioen B, Schwede F, Pannekoek WJ, Riedl J, Kooistra MRH, Jalink K, Genieser HG, Bos JL, Rehmann, H. 8-CPT-2'OMe-cAMP-AM: An improved Epac-selective cAMP analog. ChemBioChem 2008, 9:2052-2054. (PDF Article)

Paper describes an improved Epac-selective analog (007-AM) that rapidly enters cells. 


Dubé N, Kooistra MRH, Pannekoek WJ, Vliem MJ, Oorschot V, Klumperman J, Rehmann H, Bos JL. The RapGEF PDZ-GEF2 is required for the maturation of cell cell junctions. Cell Signal. 2008, 20:1608-1615. (PDF Article)

Paper describes for the first time a role for PDZ-GEF in junction formation.


Lyle KS, Raaijmakers JH, Bruinsma W, Bos JL, De Rooij J. cAMP-induced Epac-Rap1 activation inhibits epithelial cell migration by modulating focal adhesion and leading edge dynamics. Cell Signal. 2008, 20: 1104-1116. (PDF Article)

Paper describes how cAMP through Epac-Rap1 inhibits cell migration.


Rehmann H, Arias-Palomo E, Hadders MA, Schwede F, Llorca O, Bos JL. Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B. Nature 2008, 455:124-127. (PDF Article)

Paper describes the full length structure of Epac2 in the active conformation, including details of the activation mechanism.


Frische EW, Pellis-van Berkel W, van Haaften G, Cuppen E, Plasterk RH, Tijsterman M, Bos JL, Zwartkruis FJ. RAP-1 and RAL-1/exocyct pathway coordinate hypodermal cell organization in Caenorhabditis elegans. EMBO J. 2007, 26:5083-92. (PDF Article)

Paper describes a synthetic lethality between the RAP-1 and RAL-1/exocyst pathway in C. elegans.


Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: Critical elements in the control of small GTPases. Cell 2007, 129:865-877. (PubMed)


Rehmann H, Wittinghofer A, Bos JL. Capturing cyclic nucleotides in action: snapshots from crystallographic studies. Nature Rev. Mol. Cell Biol. 2007, 8: 63-73. (PDF Article)


Rehmann H, Das J, Knipscheer P, Wittinghofer A, Bos JL. Structure of the cyclic-AMP-responsive exchange factor Epac2 in its auto-inhibited state. Nature2006, 439:625-628. (PDF Article) 

Paper describes the full length structure of Epac2 in the active conformation.


Roccio M, Bos JL, Zwartkruis FJ. Regulation of the small GTPase Rheb by amino acids. Oncogene 2006, 25:657-664. (PDF Article)


Kooistra MRH, Corada M, Dejana E, Bos JL. Epac regulates integrity of endothelial junctions through VE-cadherin. FEBS Lett. 2005, 579:4966-4972. (PDF Article)

Paper describes the role of Epac in endothelial barrier function.


Pellis-van Berkel W, Verheijen MH, Cuppen E, Asahina M, de Rooij J, Jansen G, Plasterk RH, Bos JL, Zwartkruis FJ. Requirement of the Caenorhabditis elegans RapGEF pxf-1 and rap-1 for Epithelial Integrity. Mol.Biol.Cell. 2005, 16:106-116. (PDF Article)

Paper describes the role of the C. elegans PDZ-GEF homolog in epithelial integrity.


Price LS, Hajdo-Milasinovic A, Zhao J, Zwartkruis FJ, Collard, JG, Bos JL. Rap1 regulates E-cadherin-mediated cell-cell adhesion. J. Biol. Chem. 2004, 34:35127-35132. (PDF Article)

First paper to demonstrate that Rap1 regulates E-cadherin-mediated junctions in mammalian cells. 


S. Rangarajan, J.M. Enserink, H.B. Kuiperij, J. de Rooij, L.S. Price, F. Schwede, J.L. Bos. Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon stimulation of the β2-adrenergic receptor. J. Cell Biol. 2003,160:487-493. (PDF Article)

Paper shows that cAMP-induced cell adhesion is mediated by Epac1. 


Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol.Cell. 2003, 11:1457-1466. (PDF Article)


Rehmann H, Prakash B, Wolf E, Rueppel A, De Rooij J, Bos JL, Wittinghofer A. Structure and regulation of the cAMP-binding domains of Epac2. Nature Struct. Biol. 2003, 1:26-32. (PDF Article)

Paper describes the first unbound cAMP domain allowing the proposal of a universal model for cAMP-mediated activation of proteins.


J.M. Enserink, A.E. Christensen, J. de Rooij, M. van Triest, F. Schwede, H.G. Genieser, S.O. Doskeland, J.L. Blank, J.L. Bos. A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nat. Cell Biol. 2002, 4:901-906. (PDF Article)

Paper describes the development of a cAMP analog that is selective for Epac proteins. This analog, 8-CPT-2'OMe-cAMP (also called 007) is currently widely used to demonstrate Epac-mediated effects.


K.A. Reedquist, E. Ross, E.A. Koop, R.M.F. Wolthuis, F.J.T. Zwartkruis, Y. van Kooyk, M. Salmon, C.D. Buckley and J.L. Bos. The small GTPase Rap1 mediates CD31-induced integrin adhesion. J. Cell. Biol. 2000, 148:1151-1158. (PDF Article)

Paper describes the essential role of Rap1 in integrin-mediated cell adhesion. 


De Rooij J, Zwartkruis FJT, Verheijen MHG, Cool RH, Nijman SMB, Wittinghofer A, Bos JL. Epac, a Rap1 guanine nucleotide exchange factor directly activated by cAMP. Nature 1998, 396: 474-477. (PDF Article)

Paper describes the discovery of Epac proteins as novel cAMP targets.


Franke B, Akkerman JWN, Bos JL. Rapid Ca2+-mediated activation of Rap1 in human platelets. EMBO J. 1997, 16: 252-259. (PDF Article)

First paper to describe the pull-down method to detect small GTPases.