Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 3 June 2005:
Vol. 308. no. 5727, pp. 1472 - 1477
DOI: 10.1126/science.1107627
Prev | Table of Contents | Next

Reports

Mechanism of Divergent Growth Factor Effects in Mesenchymal Stem Cell Differentiation

Irina Kratchmarova,1* Blagoy Blagoev,1* Mandana Haack-Sorensen,2 Moustapha Kassem,2 Matthias Mann1{dagger}

Closely related signals often lead to very different cellular outcomes. We found that the differentiation of human mesenchymal stem cells into bone-forming cells is stimulated by epidermal growth factor (EGF) but not platelet-derived growth factor (PDGF). We used mass spectrometry–based proteomics to comprehensively compare proteins that were tyrosine phosphorylated in response to EGF and PDGF and their associated partners. More than 90% of these signaling proteins were used by both ligands, whereas the phosphatidylinositol 3-kinase (PI3K) pathway was exclusively activated by PDGF, implicating it as a possible control point. Indeed, chemical inhibition of PI3K in PDGF-stimulated cells removed the differential effect of the two growth factors, bestowing full differentiation effect onto PDGF. Thus, quantitative proteomics can directly compare entire signaling networks and discover critical differences capable of changing cell fate.

1 Center for Experimental BioInformatics (CEBI), Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
2 Department of Endocrinology, Odense University Hospital, DK-5000 Odense C, Denmark.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: mann{at}bmb.sdu.dk

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Protein Kinase C-{delta} Transactivates Platelet-derived Growth Factor Receptor-{alpha} in Mechanical Strain-induced Collagenase 3 (Matrix Metalloproteinase-13) Expression by Osteoblast-like Cells.
C.-M. Yang, H.-L. Hsieh, C.-C. Yao, L.-D. Hsiao, C.-P. Tseng, and C. B. Wu (2009)
J. Biol. Chem. 284, 26040-26050
   Abstract »    Full Text »    PDF »
Proteomics in Thyroid Tumor Research.
K. Krause, B. Jessnitzer, and D. Fuhrer (2009)
J. Clin. Endocrinol. Metab. 94, 2717-2724
   Abstract »    Full Text »    PDF »
GAREM, a Novel Adaptor Protein for Growth Factor Receptor-bound Protein 2, Contributes to Cellular Transformation through the Activation of Extracellular Signal-regulated Kinase Signaling.
K. Tashiro, T. Tsunematsu, H. Okubo, T. Ohta, E. Sano, E. Yamauchi, H. Taniguchi, and H. Konishi (2009)
J. Biol. Chem. 284, 20206-20214
   Abstract »    Full Text »    PDF »
Growth Factors, Matrices, and Forces Combine and Control Stem Cells.
D. E. Discher, D. J. Mooney, and P. W. Zandstra (2009)
Science 324, 1673-1677
   Abstract »    Full Text »    PDF »
Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Quantitative Comparison of the Membrane Proteomes of Self-renewing and Differentiating Human Embryonic Stem Cells.
T. A. Prokhorova, K. T. G. Rigbolt, P. T. Johansen, J. Henningsen, I. Kratchmarova, M. Kassem, and B. Blagoev (2009)
Mol. Cell. Proteomics 8, 959-970
   Abstract »    Full Text »    PDF »
Canonical Wnts function as potent regulators of osteogenesis by human mesenchymal stem cells.
G. Liu, S. Vijayakumar, L. Grumolato, R. Arroyave, H. Qiao, G. Akiri, and S. A. Aaronson (2009)
J. Cell Biol. 185, 67-75
   Abstract »    Full Text »    PDF »
Mechanical Signals As a Non-Invasive Means to Influence Mesenchymal Stem Cell Fate, Promoting Bone and Suppressing the Fat Phenotype.
Y. K. Luu, J. E. Pessin, S. Judex, J. Rubin, and C. T. Rubin (2009)
IBMS BoneKEy 6, 132-149
   Abstract »    Full Text »    PDF »
Identification of Receptor-Tyrosine-Kinase-Signaling Target Genes Reveals Receptor-Specific Activities and Pathway Branchpoints During Drosophila Development.
J. R. Leatherbarrow and M. S. Halfon (2009)
Genetics 181, 1335-1345
   Abstract »    Full Text »    PDF »
Fibroblast Growth Factor Receptor 2 Promotes Osteogenic Differentiation in Mesenchymal Cells via ERK1/2 and Protein Kinase C Signaling.
H. Miraoui, K. Oudina, H. Petite, Y. Tanimoto, K. Moriyama, and P. J. Marie (2009)
J. Biol. Chem. 284, 4897-4904
   Abstract »    Full Text »    PDF »
Src-dependent repression of ARF6 is required to maintain podosome-rich sealing zones in bone-digesting osteoclasts.
T. Heckel, C. Czupalla, A. I. Expirto Santo, M. Anitei, M. Arantzazu Sanchez-Fernandez, K. Mosch, E. Krause, and B. Hoflack (2009)
PNAS 106, 1451-1456
   Abstract »    Full Text »    PDF »
Sustained Platelet-Derived Growth Factor Receptor {alpha} Signaling in Osteoblasts Results in Craniosynostosis by Overactivating the Phospholipase C-{gamma} Pathway.
A. Moenning, R. Jager, A. Egert, W. Kress, E. Wardelmann, and H. Schorle (2009)
Mol. Cell. Biol. 29, 881-891
   Abstract »    Full Text »    PDF »
Comparative Phosphoproteomics of Zebrafish Fyn/Yes Morpholino Knockdown Embryos.
S. Lemeer, C. Jopling, J. Gouw, S. Mohammed, A. J. R. Heck, M. Slijper, and J. den Hertog (2008)
Mol. Cell. Proteomics 7, 2176-2187
   Abstract »    Full Text »    PDF »
Chemical and Pathway Proteomics: Powerful Tools for Oncology Drug Discovery and Personalized Health Care.
U. Kruse, M. Bantscheff, G. Drewes, and C. Hopf (2008)
Mol. Cell. Proteomics 7, 1887-1901
   Abstract »    Full Text »    PDF »
Comparisons of tyrosine phosphorylated proteins in cells expressing lung cancer-specific alleles of EGFR and KRAS.
U. Guha, R. Chaerkady, A. Marimuthu, A. S. Patterson, M. K. Kashyap, H. C. Harsha, M. Sato, J. S. Bader, A. E. Lash, J. D. Minna, et al. (2008)
PNAS 105, 14112-14117
   Abstract »    Full Text »    PDF »
Macrophage infiltration into adipose tissue may promote angiogenesis for adipose tissue remodeling in obesity.
C. Pang, Z. Gao, J. Yin, J. Zhang, W. Jia, and J. Ye (2008)
Am J Physiol Endocrinol Metab 295, E313-E322
   Abstract »    Full Text »    PDF »
PDGF, TGF-{beta}, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages.
F. Ng, S. Boucher, S. Koh, K. S. R. Sastry, L. Chase, U. Lakshmipathy, C. Choong, Z. Yang, M. C. Vemuri, M. S. Rao, et al. (2008)
Blood 112, 295-307
   Abstract »    Full Text »    PDF »
cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo.
R. Siddappa, A. Martens, J. Doorn, A. Leusink, C. Olivo, R. Licht, L. van Rijn, C. Gaspar, R. Fodde, F. Janssen, et al. (2008)
PNAS 105, 7281-7286
   Abstract »    Full Text »    PDF »
Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) and Proteome Quantitation of Mouse Embryonic Stem Cells to a Depth of 5,111 Proteins.
J. Graumann, N. C. Hubner, J. B. Kim, K. Ko, M. Moser, C. Kumar, J. Cox, H. Scholer, and M. Mann (2008)
Mol. Cell. Proteomics 7, 672-683
   Abstract »    Full Text »    PDF »
Long-term imatinib therapy promotes bone formation in CML patients.
S. Fitter, A. L. Dewar, P. Kostakis, L. B. To, T. P. Hughes, M. M. Roberts, K. Lynch, B. Vernon-Roberts, and A. C. W. Zannettino (2008)
Blood 111, 2538-2547
   Abstract »    Full Text »    PDF »
PhosphoBlast, a Computational Tool for Comparing Phosphoprotein Signatures among Large Datasets.
Y. Wang and R. L. Klemke (2008)
Mol. Cell. Proteomics 7, 145-162
   Abstract »    Full Text »    PDF »
Conditional Disruption of Calcineurin B1 in Osteoblasts Increases Bone Formation and Reduces Bone Resorption.
H. Yeo, L. H. Beck, S. R. Thompson, M. C. Farach-Carson, J. M. McDonald, T. L. Clemens, and M. Zayzafoon (2007)
J. Biol. Chem. 282, 35318-35327
   Abstract »    Full Text »    PDF »
Focal adhesion kinase regulates laminin-induced oligodendroglial process outgrowth..
N. Hoshina, T. Tezuka, K. Yokoyama, H. Kozuka-Hata, M. Oyama, and T. Yamamoto (2007)
Genes Cells 12, 1245-1254
   Abstract »    Full Text »    PDF »
PRR5, a Novel Component of mTOR Complex 2, Regulates Platelet-derived Growth Factor Receptor beta Expression and Signaling.
S.-Y. Woo, D.-H. Kim, C.-B. Jun, Y.-M. Kim, E. V. Haar, S.-i. Lee, J. W. Hegg, S. Bandhakavi, T. J. Griffin, and D.-H. Kim (2007)
J. Biol. Chem. 282, 25604-25612
   Abstract »    Full Text »    PDF »
Proteomic Analysis of Alternative Protein Tyrosine Phosphorylation in 1,2-Dichlorovinyl-Cysteine-Induced Cytotoxicity in Primary Cultured Rat Renal Proximal Tubular Cells.
M. de Graauw, S. Le Devedec, I. Tijdens, M. B. Smeets, A. M. Deelder, and B. van de Water (2007)
J. Pharmacol. Exp. Ther. 322, 89-100
   Abstract »    Full Text »    PDF »
The Tyrosine Phosphatase Shp2 Interacts with NPM-ALK and Regulates Anaplastic Lymphoma Cell Growth and Migration.
C. Voena, C. Conte, C. Ambrogio, E. Boeri Erba, F. Boccalatte, S. Mohammed, O. N. Jensen, G. Palestro, G. Inghirami, and R. Chiarle (2007)
Cancer Res. 67, 4278-4286
   Abstract »    Full Text »    PDF »
Identification of Endosomal Epidermal Growth Factor Receptor Signaling Targets by Functional Organelle Proteomics.
T. Stasyk, N. Schiefermeier, S. Skvortsov, H. Zwierzina, J. Peranen, G. K. Bonn, and L. A. Huber (2007)
Mol. Cell. Proteomics 6, 908-922
   Abstract »    Full Text »    PDF »
Multiple reaction monitoring for robust quantitative proteomic analysis of cellular signaling networks.
A. Wolf-Yadlin, S. Hautaniemi, D. A. Lauffenburger, and F. M. White (2007)
PNAS 104, 5860-5865
   Abstract »    Full Text »    PDF »
As a Matter of Fat: New Perspectives on the Understanding of Age-Related Bone Loss.
G. Duque (2007)
IBMS BoneKEy 4, 129-140
   Abstract »    Full Text »    PDF »
Proteomics Analysis of Protein Kinases by Target Class-selective Prefractionation and Tandem Mass Spectrometry.
J. Wissing, L. Jansch, M. Nimtz, G. Dieterich, R. Hornberger, G. Keri, J. Wehland, and H. Daub (2007)
Mol. Cell. Proteomics 6, 537-547
   Abstract »    Full Text »    PDF »
Distinct and Overlapping Sets of SUMO-1 and SUMO-2 Target Proteins Revealed by Quantitative Proteomics.
A. C. O. Vertegaal, J. S. Andersen, S. C. Ogg, R. T. Hay, M. Mann, and A. I. Lamond (2006)
Mol. Cell. Proteomics 5, 2298-2310
   Abstract »    Full Text »    PDF »
Primary Glioblastomas Express Mesenchymal Stem-Like Properties.
C.-L. Tso, P. Shintaku, J. Chen, Q. Liu, J. Liu, Z. Chen, K. Yoshimoto, P. S. Mischel, T. F. Cloughesy, L. M. Liau, et al. (2006)
Mol. Cancer Res. 4, 607-619
   Abstract »    Full Text »    PDF »
Suppression of the Ligand-mediated Down-regulation of Epidermal Growth Factor Receptor by Ymer, a Novel Tyrosine-phosphorylated and Ubiquitinated Protein.
K. Tashiro, H. Konishi, E. Sano, H. Nabeshi, E. Yamauchi, and H. Taniguchi (2006)
J. Biol. Chem. 281, 24612-24622
   Abstract »    Full Text »    PDF »
Graded regulation of the Kv2.1 potassium channel by variable phosphorylation..
K.-S. Park, D. P. Mohapatra, H. Misonou, and J. S. Trimmer (2006)
Science 313, 976-979
   Abstract »    Full Text »    PDF »
Phosphoproteomic analysis of Her2/neu signaling and inhibition.
R. Bose, H. Molina, A. S. Patterson, J. K. Bitok, B. Periaswamy, J. S. Bader, A. Pandey, and P. A. Cole (2006)
PNAS 103, 9773-9778
   Abstract »    Full Text »    PDF »
Ultrasensitive and absolute quantification of the phosphoinositide 3-kinase/Akt signal transduction pathway by mass spectrometry.
P. R. Cutillas, A. Khwaja, M. Graupera, W. Pearce, S. Gharbi, M. Waterfield, and B. Vanhaesebroeck (2006)
PNAS 103, 8959-8964
   Abstract »    Full Text »    PDF »
The Adaptor Protein Tom1L1 Is a Negative Regulator of Src Mitogenic Signaling Induced by Growth Factors..
M. Franco, O. Furstoss, V. Simon, C. Benistant, W. J. Hong, and S. Roche (2006)
Mol. Cell. Biol. 26, 1932-1947
   Abstract »    Full Text »    PDF »
Role of Group A p21-activated Kinases in Activation of Extracellular-regulated Kinase by Growth Factors.
A. Beeser, Z. M. Jaffer, C. Hofmann, and J. Chernoff (2005)
J. Biol. Chem. 280, 36609-36615
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)