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.
Regulation of Cell Migration by the C2 Domain of the Tumor Suppressor PTEN
Myrto Raftopoulou,
Sandrine Etienne-Manneville,
Annette Self,
Sarah Nicholls,
Alan Hall*
Abstract:
PTEN is a tumor suppressor protein that dephosphorylates phosphatidylinositol3,4,5 trisphosphate and antagonizes the phosphatidylinositol-3kinase signaling pathway. We show here that PTEN can also inhibitcell migration through its C2 domain, independent of its lipidphosphatase activity. This activity depends on the protein phosphataseactivity of PTEN and on dephosphorylation at a single residue,threonine383. The ability of PTEN to control cell migrationthrough its C2 domain is likely to be an important feature ofits tumor suppressor activity.
Medical Research Council Laboratory for Molecular Cell Biology and Cell Biology Unit, Cancer Research UK Oncogene and Signal Transduction Group, and Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.
* To whom correspondence should be addressed. E-mail: alan.hall{at}ucl.ac.uk
The editors suggest the following Related Resources on Science sites:
G. Zhu, L. M. L. Chow, I. T. Bayazitov, Y. Tong, R. J. Gilbertson, S. S. Zakharenko, D. J. Solecki, and S. J. Baker (2012)
Development
139, 3422-3431
|Abstract »|Full Text »|PDF »
Inhibition of Mycobacterial Infection by the Tumor Suppressor PTEN.
G. Huang, G. Redelman-Sidi, N. Rosen, M. S. Glickman, and X. Jiang (2012)
J. Biol. Chem.
287, 23196-23202
|Abstract »|Full Text »|PDF »
Haploinsufficiency of the genes encoding the tumor suppressor Pten predisposes zebrafish to hemangiosarcoma.
S. Choorapoikayil, R. V. Kuiper, A. de Bruin, and J. den Hertog (2012)
Dis. Model. Mech.
5, 241-247
|Abstract »|Full Text »|PDF »
PTEN Protein Phosphatase Activity Correlates with Control of Gene Expression and Invasion, a Tumor-Suppressing Phenotype, But Not with AKT Activity.
P. Tibarewal, G. Zilidis, L. Spinelli, N. Schurch, H. Maccario, A. Gray, N. M. Perera, L. Davidson, G. J. Barton, and N. R. Leslie (2012)
Science Signaling
5, ra18
|Abstract »|Full Text »|PDF »
N-cadherin expression level modulates integrin-mediated polarity and strongly impacts on the speed and directionality of glial cell migration.
E. Camand, F. Peglion, N. Osmani, M. Sanson, and S. Etienne-Manneville (2012)
J. Cell Sci.
125, 844-857
|Abstract »|Full Text »|PDF »
PTEN Directly Activates the Actin Depolymerization Factor Cofilin-1 During PGE2-Mediated Inhibition of Phagocytosis of Fungi.
C. H. Serezani, S. Kane, A. I. Medeiros, A. M. Cornett, S.-H. Kim, M. M. Marques, S.-P. Lee, C. Lewis, E. Bourdonnay, M. N. Ballinger, et al. (2012)
Science Signaling
5, ra12
|Abstract »|Full Text »|PDF »
PTEN Regulation of Local and Long-Range Connections in Mouse Auditory Cortex.
Q. Xiong, H. V. Oviedo, L. C. Trotman, and A. M. Zador (2012)
J. Neurosci.
32, 1643-1652
|Abstract »|Full Text »|PDF »
Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia.
J. Howitt, J. Lackovic, L.-H. Low, A. Naguib, A. Macintyre, C.-P. Goh, J. K. Callaway, V. Hammond, T. Thomas, M. Dixon, et al. (2012)
J. Cell Biol.
196, 29-36
|Abstract »|Full Text »|PDF »
Targeting the mTOR/4E-BP Pathway in Endometrial Cancer.
S. B. Korets, S. Czok, S. V. Blank, J. P. Curtin, and R. J. Schneider (2011)
Clin. Cancer Res.
17, 7518-7528
|Abstract »|Full Text »|PDF »
Platelet-derived Growth Factor (PDGF) Regulates Slingshot Phosphatase Activity via Nox1-dependent Auto-dephosphorylation of Serine 834 in Vascular Smooth Muscle Cells.
M. Maheswaranathan, H. K. A. Gole, I. Fernandez, B. Lassegue, K. K. Griendling, and A. San Martin (2011)
J. Biol. Chem.
286, 35430-35437
|Abstract »|Full Text »|PDF »
Mechanistic Analysis of a DNA Damage-Induced, PTEN-Dependent Size Checkpoint in Human Cells.
J.-S. Kim, X. Xu, H. Li, D. Solomon, W. S. Lane, T. Jin, and T. Waldman (2011)
Mol. Cell. Biol.
31, 2756-2771
|Abstract »|Full Text »|PDF »
Protein Interactions of Phosphatase and Tensin Homologue (PTEN) and Its Cancer-associated G20E Mutant Compared by Using Stable Isotope Labeling by Amino Acids in Cell Culture-based Parallel Affinity Purification.
J. Gunaratne, M. X. Goh, H. L. F. Swa, F. Y. Lee, E. Sanford, L. M. Wong, K. A. Hogue, W. P. Blackstock, and K. Okumura (2011)
J. Biol. Chem.
286, 18093-18103
|Abstract »|Full Text »|PDF »
Doubles Game: Src-Stat3 versus p53-PTEN in Cellular Migration and Invasion.
U. K. Mukhopadhyay, P. Mooney, L. Jia, R. Eves, L. Raptis, and A. S. Mak (2010)
Mol. Cell. Biol.
30, 4980-4995
|Abstract »|Full Text »|PDF »
PTEN regulates angiogenesis and VEGF expression through phosphatase-dependent and -independent mechanisms in HepG2 cells.
T. Tian, K.-J. Nan, S.-H. Wang, X. Liang, C.-X. Lu, H. Guo, W.-J. Wang, and Z.-P. Ruan (2010)
Carcinogenesis
31, 1211-1219
|Abstract »|Full Text »|PDF »
Tumor Suppression by PTEN Requires the Activation of the PKR-eIF2{alpha} Phosphorylation Pathway.
Z. Mounir, J. L. Krishnamoorthy, G. P. Robertson, D. Scheuner, R. J. Kaufman, M.-M. Georgescu, and A. E. Koromilas (2009)
Science Signaling
2, ra85
|Abstract »|Full Text »|PDF »
Role of Rap1B and Tumor Suppressor PTEN in the Negative Regulation of Lysophosphatidic Acid--induced Migration by Isoproterenol in Glioma Cells.
E. Malchinkhuu, K. Sato, T. Maehama, S. Ishiuchi, Y. Yoshimoto, C. Mogi, T. Kimura, H. Kurose, H. Tomura, and F. Okajima (2009)
Mol. Biol. Cell
20, 5156-5165
|Abstract »|Full Text »|PDF »
Analysis of PTEN Complex Assembly and Identification of Heterogeneous Nuclear Ribonucleoprotein C as a Component of the PTEN-associated Complex.
S. Mosessian, N. K. Avliyakulov, D. J. Mulholland, P. Boontheung, J. A. Loo, and H. Wu (2009)
J. Biol. Chem.
284, 30159-30166
|Abstract »|Full Text »|PDF »
Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes.
D. K. Finlay, L. V. Sinclair, C. Feijoo, C. M. Waugh, T. J. Hagenbeek, H. Spits, and D. A. Cantrell (2009)
J. Exp. Med.
206, 2441-2454
|Abstract »|Full Text »|PDF »
p85 Associates with Unphosphorylated PTEN and the PTEN-Associated Complex.
R. Rabinovsky, P. Pochanard, C. McNear, S. M. Brachmann, J. S. Duke-Cohan, L. A. Garraway, and W. R. Sellers (2009)
Mol. Cell. Biol.
29, 5377-5388
|Abstract »|Full Text »|PDF »
Cell type specificity of PI3K signaling in Pdk1- and Pten-deficient brains.
N. Chalhoub, G. Zhu, X. Zhu, and S. J. Baker (2009)
Genes & Dev.
23, 1619-1624
|Abstract »|Full Text »|PDF »
Loss of Phosphatase and Tensin Homologue Deleted on Chromosome 10 Engages ErbB3 and Insulin-Like Growth Factor-I Receptor Signaling to Promote Antiestrogen Resistance in Breast Cancer.
T. W. Miller, M. Perez-Torres, A. Narasanna, M. Guix, O. Stal, G. Perez-Tenorio, A. M. Gonzalez-Angulo, B. T. Hennessy, G. B. Mills, J. P. Kennedy, et al. (2009)
Cancer Res.
69, 4192-4201
|Abstract »|Full Text »|PDF »
Pten Deletion in Adult Neural Stem/Progenitor Cells Enhances Constitutive Neurogenesis.
C. Gregorian, J. Nakashima, J. Le Belle, J. Ohab, R. Kim, A. Liu, K. B. Smith, M. Groszer, A. D. Garcia, M. V. Sofroniew, et al. (2009)
J. Neurosci.
29, 1874-1886
|Abstract »|Full Text »|PDF »
RhoA-Dependent Regulation of Cell Migration by the Tumor Suppressor hSNF5/INI1.
Molecular Pathways Regulating Pro-migratory Effects of Hedgehog Signaling.
E. Hochman, A. Castiel, J. Jacob-Hirsch, N. Amariglio, and S. Izraeli (2006)
J. Biol. Chem.
281, 33860-33870
|Abstract »|Full Text »|PDF »
Nuclear Localization of PTEN by a Ran-dependent Mechanism Enhances Apoptosis: Involvement of an N-Terminal Nuclear Localization Domain and Multiple Nuclear Exclusion Motifs.
A. Gil, A. Andres-Pons, E. Fernandez, M. Valiente, J. Torres, J. Cervera, and R. Pulido (2006)
Mol. Biol. Cell
17, 4002-4013
|Abstract »|Full Text »|PDF »
PTEN Deletion Leads to Up-regulation of a Secreted Growth Factor Pleiotrophin.
G. Li, Y. Hu, Y. Huo, M. Liu, D. Freeman, J. Gao, X. Liu, D.-C. Wu, and H. Wu (2006)
J. Biol. Chem.
281, 10663-10668
|Abstract »|Full Text »|PDF »
Tumor suppressor PTEN acts through dynamic interaction with the plasma membrane..
F. Vazquez, S. Matsuoka, W. R. Sellers, T. Yanagida, M. Ueda, and P. N. Devreotes (2006)
PNAS
103, 3633-3638
|Abstract »|Full Text »|PDF »
PTEN couples Sema3A signalling to growth cone collapse.
N. H. Chadborn, A. I. Ahmed, M. R. Holt, R. Prinjha, G. A. Dunn, G. E. Jones, and B. J. Eickholt (2006)
J. Cell Sci.
119, 951-957
|Abstract »|Full Text »|PDF »
High Frequency of Coexistent Mutations of PIK3CA and PTEN Genes in Endometrial Carcinoma.
K. Oda, D. Stokoe, Y. Taketani, and F. McCormick (2005)
Cancer Res.
65, 10669-10673
|Abstract »|Full Text »|PDF »
TGF{beta}-induced downregulation of E-cadherin-based cell-cell adhesion depends on PI3-kinase and PTEN.
R. Vogelmann, M.-D. Nguyen-tat, K. Giehl, G. Adler, D. Wedlich, and A. Menke (2005)
J. Cell Sci.
118, 4901-4912
|Abstract »|Full Text »|PDF »
Negative regulation of CXCR4-mediated chemotaxis by the lipid phosphatase activity of tumor suppressor PTEN.
P. Gao, R. L. Wange, N. Zhang, J. J. Oppenheim, and O. M. Z. Howard (2005)
Blood
106, 2619-2626
|Abstract »|Full Text »|PDF »
Mutations of Phosphatase and Tensin Homolog Deleted from Chromosome 10 in Canine Hemangiosarcoma.
E. B. Dickerson, R. Thomas, S. P. Fosmire, A. R. Lamerato-Kozicki, S. R. Bianco, J. W. Wojcieszyn, M. Breen, S. C. Helfand, and J. F. Modiano (2005)
Veterinary Pathology
42, 618-632
|Abstract »|Full Text »|PDF »
Different splicing defects lead to differential effects downstream of the lipid and protein phosphatase activities of PTEN.
Binding of PTEN to Specific PDZ Domains Contributes to PTEN Protein Stability and Phosphorylation by Microtubule-associated Serine/Threonine Kinases.
M. Valiente, A. Andres-Pons, B. Gomar, J. Torres, A. Gil, C. Tapparel, S. E. Antonarakis, and R. Pulido (2005)
J. Biol. Chem.
280, 28936-28943
|Abstract »|Full Text »|PDF »
LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes.
H. Mehenni, N. Lin-Marq, K. Buchet-Poyau, A. Reymond, M. A. Collart, D. Picard, and S. E. Antonarakis (2005)
Hum. Mol. Genet.
14, 2209-2219
|Abstract »|Full Text »|PDF »
Nuclear PTEN-Mediated Growth Suppression Is Independent of Akt Down-Regulation.
J.-L. Liu, X. Sheng, Z. K. Hortobagyi, Z. Mao, G. E. Gallick, and W. K. A. Yung (2005)
Mol. Cell. Biol.
25, 6211-6224
|Abstract »|Full Text »|PDF »
PTEN deletion in Bergmann glia leads to premature differentiation and affects laminar organization.
Q. Yue, M. Groszer, J. S. Gil, A. J. Berk, A. Messing, H. Wu, and X. Liu (2005)
Development
132, 3281-3291
|Abstract »|Full Text »|PDF »
Somatic Induction of Pten Loss in a Preclinical Astrocytoma Model Reveals Major Roles in Disease Progression and Avenues for Target Discovery and Validation.
A. Xiao, C. Yin, C. Yang, A. Di Cristofano, P. P. Pandolfi, and T. Van Dyke (2005)
Cancer Res.
65, 5172-5180
|Abstract »|Full Text »|PDF »
PIK3CA Mutations Correlate with Hormone Receptors, Node Metastasis, and ERBB2, and Are Mutually Exclusive with PTEN Loss in Human Breast Carcinoma.
L. H. Saal, K. Holm, M. Maurer, L. Memeo, T. Su, X. Wang, J. S. Yu, P.-O. Malmstrom, M. Mansukhani, J. Enoksson, et al. (2005)
Cancer Res.
65, 2554-2559
|Abstract »|Full Text »|PDF »
PTEN as an effector in the signaling of antimigratory G protein-coupled receptor.
T. Sanchez, S. Thangada, M.-T. Wu, C. D. Kontos, D. Wu, H. Wu, and T. Hla (2005)
PNAS
102, 4312-4317
|Abstract »|Full Text »|PDF »
Phosphatase and tensin homologue growth suppression without phosphatase.
D. Stokoe and J. F. Costello (2005)
PNAS
102, 2677-2678
|Full Text »|PDF »
Cellular transformation by the MSP58 oncogene is inhibited by its physical interaction with the PTEN tumor suppressor.
K. Okumura, M. Zhao, R. A. DePinho, F. B. Furnari, and W. K. Cavenee (2005)
PNAS
102, 2703-2706
|Abstract »|Full Text »|PDF »
Vinculin Controls PTEN Protein Level by Maintaining the Interaction of the Adherens Junction Protein {beta}-Catenin with the Scaffolding Protein MAGI-2.
M. C. Subauste, P. Nalbant, E. D. Adamson, and K. M. Hahn (2005)
J. Biol. Chem.
280, 5676-5681
|Abstract »|Full Text »|PDF »
Prostaglandin E2 Inhibits Fibroblast Migration by E-Prostanoid 2 Receptor-Mediated Increase in PTEN Activity.
E. S. White, R. G. Atrasz, E. G. Dickie, D. M. Aronoff, V. Stambolic, T. W. Mak, B. B. Moore, and M. Peters-Golden (2005) 32, 135-141
|Abstract »|Full Text »|PDF »
PTEN regulates motility but not directionality during leukocyte chemotaxis.
R. A. Lacalle, C. Gomez-Mouton, D. F. Barber, S. Jimenez-Baranda, E. Mira, C. Martinez-A., A. C. Carrera, and S. Manes (2004)
J. Cell Sci.
117, 6207-6215
|Abstract »|Full Text »|PDF »
Pten Loss Causes Hypertrophy and Increased Proliferation of Astrocytes In vivo.
M. M. Fraser, X. Zhu, C.-H. Kwon, E. J. Uhlmann, D. H. Gutmann, and S. J. Baker (2004)
Cancer Res.
64, 7773-7779
|Abstract »|Full Text »|PDF »
Regulation of PTEN Phosphorylation and Stability by a Tumor Suppressor Candidate Protein.
F. Okahara, H. Ikawa, Y. Kanaho, and T. Maehama (2004)
J. Biol. Chem.
279, 45300-45303
|Abstract »|Full Text »|PDF »
Phospholipase C and cofilin are required for carcinoma cell directionality in response to EGF stimulation.
G. Mouneimne, L. Soon, V. DesMarais, M. Sidani, X. Song, S.-C. Yip, M. Ghosh, R. Eddy, J. M. Backer, and J. Condeelis (2004)
J. Cell Biol.
166, 697-708
|Abstract »|Full Text »|PDF »