Function: Assistant professor
Address (work):
Department of Metabolic Diseases
University Medical Center Utrecht
Room KC.02.069.1
Lundlaan 6
3584 EA Utrecht
The Netherlands
phone: 088 - 75 543 37 (lab) / 75 542 93 (office)
e-mail:
S.vandeGraaf-4@umcutrecht.nl2009-presentAssistant-professor at the Department of Metabolic and Endocrine diseases, University Medical Center Utrecht, The Netherlands on a Veni grant from the The Netherlands Organisation for Scientific Research
2007-2009Post-doc at the Department of Metabolic and Endocrine diseases, University Medical Center Utrecht, The Netherlands on a WKZ fund
2006-2007Post-doctoral fellow at the Institute of Medical Biochemistry, University of Muenster, Germany on a Long-term EMBO Fellowship
2005-2006Post-doctoral fellow at the Institute of Medical Biochemistry, University of Muenster, Germany on a Talent Stipendium
2001Collaborative visitor of the Institute of Pharmacology and Toxicology, University of Lausanne, Switserland
2000-2004
PhD student at the Department of Physiology, University Medical Centre Nijmegen, the Netherlands
2000Research trainee at the Department of Cell Biology and Physiology, University of Pittsburgh, USA
2006 Best Ph.D. thesis of 2005, Dutch Nephrology Society and Dutch Kidney Foundation
2005 Recipient of the "Jacob Hamburger" prize for the best thesis in 2005, Dutch Physiology Society
2010 NGI Horizon grant
2010 Wilhelmina Childrens Hospital Fund
2008 Veni grant from the Netherlands Organization for Scientific Research
2005 Long-term EMBO fellowship
2005 “Talent“ stipendium Netherlands Organization for Scientific Research
2010-2011 Supervisor for compact intership of bachelor students Biomedical Sciences, University of Utrecht, Topic ‘Stofwisseling’
2008-2010 Teacher for Project 2; Biomedical Sciences, University of Utrecht
2004, 2007-2010 Supervisor for bachelor and master students, Hogeschool van Arnhem en Nijmegen, Radboud University Nijmegen,
University of Utrecht
2008-present Coördinator for the selection, installation and operation of the WKZ confocal microscopy setup
The research group of Stan van de Graaf is interested in the regulation of various transporter proteins that together maintain the bile salt balance. Bile salt (BS) homeostasis is pivotal for the absorption of dietary fats and fat-soluble vitamins in the intestine, for cholesterol metabolism and is linked to triglyceride and glucose homeostasis. Impaired hepatic BS secretion results in cholestasis and constitutes a major cause of liver failure, since accumulated BSs are cytotoxic. The BS balance is maintained in a fascinating interplay between hepatic and intestinal transport processes, called the enterohepatic circulation of bile salts (Figure 1).
Na+-dependent BS absorption into enterocytes and cholangiocytes is mediated by a specific transport protein named Apical Sodium Bile Transporter (ASBT), whereas BSs are cleared from the portal blood by hepatocytes mainly via the Sodium Taurocholate Cotransporting Polypeptide (NTCP). Therefore, the dynamic regulation of ASBT and NTCP is pivotal to control hepatic and intestinal BS uptake and to regulate bile salt homeostasis. We study the post-translational regulation of these transporter using a variety of techniques, including confocal microscopy, biochemical characterization of transporter trafficking using a combination of cell surface biotinylation and mesna-assays, Functional recovery after chemobleaching, and several functional assays.
Besides cellular BS influx, we also study defects in BS efflux related to impaired bile flow or cholestasis. Cholestasis is a very common and destructive manifestation of hereditary liver disease. Intrahepatic cholestasis is genetically heterogeneous. Mutations in at least three genes, BSEP, MDR3 and ATP8B1, can lead to familial progressive cholestasis. ATP8B1 deficiency results in intrahepatic cholestasis with variable severity from severe pruritus to life-threatening progressive liver damage. Importantly, for a large percentage of patients, the genetic cause of cholestasis remains unknown. We aim to open new areas of diagnosis, research and future treatment of familial intrahepatic cholestasis by 1) elucidation of novel ATP8B1 regulatory pathways, 2) Identification of pharmacological chaperones that correct ATP8B1 midfolding and 3) identification of novel candidate genes to genetically explain the cholestatic phenotype of patients without known transporter gene defects.
Besides the relevance to bile salt homeostasis, the significance of my studies further spreads to other transport proteins that are expressed in polarized cells. These cells have two distinct plasma membrane domains with specific composition; the apical plasma membrane and the basolateral plasma membrane. These membranes form the barrier between either the lumen (apical) or the blood (basolateral) and the cell interior. Cells are able to specifically regulate the abundance of various transporting proteins in these plasma membrane compartments. This enables the cells to specifically control the transport of a variety of molecules from one side of the cell to the other. In the past, my work has mainly focussed on how a cell is able to maintain the correct amount of TRPV5 and TRPV6 on the correct plasma membrane compartment. In the near future I will focuss on bile salt transport proteins to eventually be able to come to more generalized predictions and advanced insight in (patho)physiological processes related to membrane transport proteins.
Ingrid Bijsmans, PhD
Wendy van der Woerd, MD
Rina Wichers, Bsc
Lynn van Gent, HLO student
Bijsmans IT, Bouwmeester RA, Geyer J, Faber KN,
van de Graaf SF.
Homo- and hetero-dimeric architecture of the human liver Na+-dependent taurocholate co-transporting protein.
Biochem J. 2012 Feb 1;441(3):1007-15.
van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW,
van de Graaf SF, Houwen RH.
Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy.
Best Pract Res Clin Gastroenterol. 2010 Oct;24(5):541-53
Van der Velden LM, Wichers CG, van Breevoort AE, Coleman JA, Molday RS, Berger R, Klomp LW,
van de Graaf SF.
Heteromeric interactions required for abundance and subcellular localization of human CDC50 proteins and class 1 P4 ATPases.
J Biol Chem 2010 Dec 17;285(51):40088-96
Van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW,
van de Graaf SF, Houwen RH.
Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy.
Best Pract Res Clin Gastroenterol, 24,541-53. 2010
van der Velden LM,
van de Graaf SF, Klomp LW.
Biochemical and cellular functions of P4 ATPases.
Biochem J. 431, 1-11, 2010
Van der Velden LM*, Stapelbroek JM*, Krieger E, Van den Berghe PV, Berger R, Holthuis JC, Houwen RH, Klomp LW#,
Van de Graaf SF#
Folding defects in ATP8B1 associated with hereditary cholestasis are ameliorated by 4-phenylbutyrate
Hepatology, 51, 286-96, 2010 *,# contributed equally
Van den Berghe PV, Stapelbroek JM, Krieger E, De Bie P,
Van de Graaf SF, De Groot RE , Van Beurden E, Spijker E, Houwen RH, Berger R, Klomp LW
Reduced expression of ATP7B affected by Wilson disease-causing mutations is rescued by pharmacological folding chaperones 4-phenylbutyrate and curcumin
Hepatology, 50, 1783-95, 2009
Schoeber JP*,
Van de Graaf SF*, Lee KP, Wittgen HG, Hoenderop JG, Bindels RJ.
Conditional fast expression and function of multimeric TRPV5 channels using Shield-1
Am J Physiol Renal Physiol, 296, F204-11, 2009 * contributed equally
Van de Graaf SF, Rescher U, Hoenderop JG, Bindels RJ, Gerke V.
TRPV5 is internalized via clathrin-dependent endocytosis to enter a Ca2+-controlled recycling pathway
J Biol Chem. 283, 4077-86, 2008
Van de Graaf SF, Bindels RJ, Hoenderop JG.
Epithelial Ca2+ and Mg2+ transport
Rev Physiol Biochem Pharmacol. 158, 77-160, 2007
Van de Graaf SF, Hoenderop JG, Bindels RJ.
Regulation of TRPV5 and TRPV6 by associated proteins.
Am J Physiol Renal Physiol. 290, F1295-302, 2006
Van de Graaf SF, Hoenderop JG, Van der Kemp AW, Gisler SM, Bindels RJ.
Interaction of the epithelial Ca2+ channels TRPV5 and TRPV6 with the intestine- and kidney-enriched PDZ protein NHERF4.
Pflugers Arch. 452, 407-17, 2006
Van de Graaf SF, Van der Kemp AW, Van den Berg D, Van Oorschot M, Hoenderop JG, Bindels RJ.
Identification of BSPRY as a novel auxiliary protein inhibiting TRPV5 activity.
J Am Soc Nephrol. 17, 26-30, 2006
Van de Graaf SF, Chang Q, Mensenkamp AR, Hoenderop JG, Bindels RJ.
Direct interaction with Rab11a targets the epithelial Ca2+ channels TRPV5 and TRPV6 to the plasma membrane.
Mol Cell Biol. 26, 303-12, 2006
Den Dekker E, Schoeber J, Topala C,
Van de Graaf SF, Hoenderop JG, Bindels RJ.
Characterization of a Madin-Darby Canine Kidney cell line stably expressing TRPV5
Pflugers Arch. 450, 236-44, 2005
Chang Q, Gyftogianni E,
Van de Graaf SF, Hoefs S, Weidema F, Bindels RJ, Hoenderop JG.
Molecular determinants in TRPV5 channel assembly
J Biol Chem. 279, 54304-11, 2004
Palmada M, Setiawan I, Poppendieck S, Embark HM,
Van de Graaf SF, Boehmer C, Gerstberger R, Cohen P, Yun CC, Bindels RJ, Lang F.
Requirement of PDZ domains for the stimulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase SGK1
Cell Physiol Biochem. 15, 175-82, 2005
Embark HM, Setiawan I, Poppendieck S,
Van de Graaf SF, Boehmer C, Palmada M, Gerstberger R, Cohen P, Yun CC, Bindels RJ, Lang F.
Regulation of the epithelial Ca2+ channel TRPV5 by the NHE regulating factor NHERF2 and the serum and glucocorticoid inducible kinase isoforms SGK1 and SGK3 expressed in Xenopus oocytes.
Cell Physiol Biochem. 14, 203-12, 2004
Van de Graaf SF, Boullart I, Hoenderop JG, Bindels RJ.
Regulation of the epithelial Ca2+ channels TRPV5 and TRPV6 by 1a,25-dihydroxivitamin D3 and dietary Ca2+.
J Steroid Biochem Mol Biol. 89-90,303-8, 2004
Van de Graaf SF, Hoenderop JG, Gkika D, Lamers D, Prenen J, Rescher U, Gerke V, Staub O, Nilius B, Bindels RJ.
Functional expression of the epithelial Ca2+ channels (TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex.
EMBO J. 22,1478-87, 2003
Danahay H, Withey L, Poll CT,
Van de Graaf SF, Bridges RJ.
Protease-activated receptor-2-mediated inhibition of ion transport in human bronchial epithelial cells.
Am J Physiol Cell Physiol. 280, C1455-64, 2001
Hoenderop JG, van der Kemp AW, Hartog A,
Van de Graaf SF, van Os CH, Willems PH,
Bindels RJ.
Molecular identification of the apical Ca2+ channel in 1, 25-dihydroxyvitamin D3-responsive epithelia.
J Biol Chem. 274, 8375-8, 1999
Stapelbroek JM, Van der Velden LM,
Van de Graaf SF, Klomp LW, Houwen RH.
In: ATP8B1 deficiency: general background, clinical manifestations and possible therapeutic interventions. D. Keppler, U Beuers, A steihl, M Trauner, eds. Bile acid biology and therapeutic actions, series Falk symposium 2009, Vol 165; Chapter 34