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.


Logo for

J. Cell Biol. 147 (6): 1129-1136

Copyright © 1999 by the Rockefeller University Press.

Brief Report

A Novel Regulatory Mechanism of Map Kinases Activation and Nuclear Translocation Mediated by Pka and the Ptp-Sl Tyrosine Phosphatase

Carmen Blanco-Aparicioa, Josema Torresa, , and Rafael Pulidoa

a Instituto de Investigaciones Citológicas, 46010 Valencia, Spain
Instituto de Investigaciones Citológicas, Amadeo de Saboya, 4, 46010 Valencia, Spain.34-96-360145334-96-3391256


Abstract: Protein tyrosine phosphatase PTP-SL retains mitogen-activated protein (MAP) kinases in the cytoplasm in an inactive form by association through a kinase interaction motif (KIM) and tyrosine dephosphorylation. The related tyrosine phosphatases PTP-SL and STEP were phosphorylated by the cAMP-dependent protein kinase A (PKA). The PKA phosphorylation site on PTP-SL was identified as the Ser231 residue, located within the KIM. Upon phosphorylation of Ser231, PTP-SL binding and tyrosine dephosphorylation of the MAP kinases extracellular signal–regulated kinase (ERK)1/2 and p38{alpha} were impaired. Furthermore, treatment of COS-7 cells with PKA activators, or overexpression of the C{alpha} catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38{alpha} by wild-type PTP-SL, but not by a PTP-SL S231A mutant. These findings support the existence of a novel mechanism by which PKA may regulate the activation and translocation to the nucleus of MAP kinases.

Key Words: MAP kinases • PKA • PTP-SL • tyrosine phosphatases • signal transduction

C. Blanco-Aparicio and J. Torres contributed equally to this work.

Abbreviations used in this paper: cPKA, PKA catalytic subunit; ERK, extracellular signal–regulated kinase; GST, glutathione-S-transferase; HA, hemagglutinin; JNK, c-Jun NH2-terminal kinase; KIM, kinase interaction motif; MAP, mitogen-activated protein; PKA, protein kinase A; PKC, protein kinase C; PTP, protein tyrosine phosphatase.

Interconnected Network Motifs Control Podocyte Morphology and Kidney Function.
E. U. Azeloglu, S. V. Hardy, N. J. Eungdamrong, Y. Chen, G. Jayaraman, P. Y. Chuang, W. Fang, H. Xiong, S. R. Neves, M. R. Jain, et al. (2014)
Science Signaling 7, ra12
   Abstract »    Full Text »    PDF »
A High-throughput Assay for Phosphoprotein-specific Phosphatase Activity in Cellular Extracts.
A. K. Bose and K. A. Janes (2013)
Mol. Cell. Proteomics 12, 797-806
   Abstract »    Full Text »    PDF »
Phosphorylation of the Kinase Interaction Motif in Mitogen-activated Protein (MAP) Kinase Phosphatase-4 Mediates Cross-talk between Protein Kinase A and MAP Kinase Signaling Pathways.
R. J. Dickinson, L. Delavaine, R. Cejudo-Marin, G. Stewart, C. J. Staples, M. P. Didmon, A. G. Trinidad, A. Alonso, R. Pulido, and S. M. Keyse (2011)
J. Biol. Chem. 286, 38018-38026
   Abstract »    Full Text »    PDF »
Working Without Kinase Activity: Phosphotransfer-Independent Functions of Extracellular Signal-Regulated Kinases.
J. Rodriguez and P. Crespo (2011)
Science Signaling 4, re3
   Abstract »    Full Text »    PDF »
Mechanism of Sustained Activation of Ribosomal S6 Kinase (RSK) and ERK by Kaposi Sarcoma-associated Herpesvirus ORF45: MULTIPROTEIN COMPLEXES RETAIN ACTIVE PHOSPHORYLATED ERK AND RSK AND PROTECT THEM FROM DEPHOSPHORYLATION.
E. Kuang, F. Wu, and F. Zhu (2009)
J. Biol. Chem. 284, 13958-13968
   Abstract »    Full Text »    PDF »
A Cross-Link between Protein Kinase A and Rho-Family GTPases Signaling Mediates Cell-Cell Adhesion and Actin Cytoskeleton Organization in Epithelial Cancer Cells.
F. Leve, W. de Souza, and J. A. Morgado-Diaz (2008)
J. Pharmacol. Exp. Ther. 327, 777-788
   Abstract »    Full Text »    PDF »
Calcium-mediated Interactions Regulate the Subcellular Localization of Extracellular Signal-regulated Kinases.
D. Chuderland, G. Marmor, A. Shainskaya, and R. Seger (2008)
J. Biol. Chem. 283, 11176-11188
   Abstract »    Full Text »    PDF »
Mxi2 promotes stimulus-independent ERK nuclear translocation.
B. Casar, V. Sanz-Moreno, M. N. Yazicioglu, J. Rodriguez, M. T. Berciano, M. Lafarga, M. H. Cobb, and P. Crespo (2007)
EMBO J. 26, 635-646
   Abstract »    Full Text »    PDF »
ERK2 Shows a Restrictive and Locally Selective Mechanism of Recognition by Its Tyrosine Phosphatase Inactivators Not Shared by Its Activator MEK1.
C. Tarrega, P. Rios, R. Cejudo-Marin, C. Blanco-Aparicio, L. van den Berk, J. Schepens, W. Hendriks, L. Tabernero, and R. Pulido (2005)
J. Biol. Chem. 280, 37885-37894
   Abstract »    Full Text »    PDF »
cAMP-dependent Protein Kinase Type I Regulates Ethanol-induced cAMP Response Element-mediated Gene Expression via Activation of CREB-binding Protein and Inhibition of MAPK.
A. Constantinescu, M. Wu, O. Asher, and I. Diamond (2004)
J. Biol. Chem. 279, 43321-43329
   Abstract »    Full Text »    PDF »
SU1498, an Inhibitor of Vascular Endothelial Growth Factor Receptor 2, Causes Accumulation of Phosphorylated ERK Kinases and Inhibits Their Activity in Vivo and in Vitro.
G. Boguslawski, P. W. McGlynn, K. A. Harvey, and A. T. Kovala (2004)
J. Biol. Chem. 279, 5716-5724
   Abstract »    Full Text »    PDF »
Rosmarinic acid inhibits Ca2+-dependent pathways of T-cell antigen receptor-mediated signaling by inhibiting the PLC-gamma 1 and Itk activity.
M.-A. Kang, S.-Y. Yun, and J. Won (2003)
Blood 101, 3534-3542
   Abstract »    Full Text »    PDF »
Importin-alpha Mediates the Regulated Nuclear Targeting of Serum- and Glucocorticoid-inducible Protein Kinase (Sgk) by Recognition of a Nuclear Localization Signal in the Kinase Central Domain.
A. C. Maiyar, M. L.L. Leong, and G. L. Firestone (2003)
Mol. Biol. Cell 14, 1221-1239
   Abstract »    Full Text »    PDF »
Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy.
R. Dash, A. G Schmidt, A. Pathak, M. J Gerst, D. Biniakiewicz, V. J Kadambi, B. D Hoit, W. T Abraham, and E. G Kranias (2003)
Cardiovasc Res 57, 704-714
   Abstract »    Full Text »    PDF »
Follicle-stimulating Hormone Activates Extracellular Signal-regulated Kinase but Not Extracellular Signal-regulated Kinase Kinase through a 100-kDa Phosphotyrosine Phosphatase.
J. Cottom, L. M. Salvador, E. T. Maizels, S. Reierstad, Y. Park, D. W. Carr, M. A. Davare, J. W. Hell, S. S. Palmer, P. Dent, et al. (2003)
J. Biol. Chem. 278, 7167-7179
   Abstract »    Full Text »    PDF »
cAMP-dependent Protein Kinase and Ca2+Influx through L-type Voltage-gated Calcium Channels Mediate Raf-independent Activation of Extracellular Regulated Kinase in Response to Glucagon-like Peptide-1 in Pancreatic {beta}-Cells.
E. Gomez, C. Pritchard, and T. P. Herbert (2002)
J. Biol. Chem. 277, 48146-48151
   Abstract »    Full Text »    PDF »
Binding of JNK/SAPK to MEKK1 Is Regulated by Phosphorylation.
E. D. Gallagher, S. Xu, C. Moomaw, C. A. Slaughter, and M. H. Cobb (2002)
J. Biol. Chem. 277, 45785-45792
   Abstract »    Full Text »    PDF »
Modulation of Gene Expression by the MHC Class II Transactivator.
U. M. Nagarajan, A. Bushey, and J. M. Boss (2002)
J. Immunol. 169, 5078-5088
   Abstract »    Full Text »    PDF »
Nuclear import of factors involved in signaling is inhibited in C3H/10T1/2 cells treated with tetradecylthioacetic acid.
B. Bjorndal, C. Helleland, S.-O. Boe, O. A. Gudbrandsen, K.-H. Kalland, P. Bohov, R. K. Berge, and J. R. Lillehaug (2002)
J. Lipid Res. 43, 1630-1640
   Abstract »    Full Text »    PDF »
Phosphotyrosine-specific Phosphatase PTP-SL Regulates the ERK5 Signaling Pathway.
M. Buschbeck, J. Eickhoff, M. N. Sommer, and A. Ullrich (2002)
J. Biol. Chem. 277, 29503-29509
   Abstract »    Full Text »    PDF »
D1 Dopamine Receptor Regulation of Microtubule-Associated Protein-2 Phosphorylation in Developing Cerebral Cortical Neurons.
Z.-M. Song, A. S. Undie, P. O. Koh, Y.-Y. Fang, L. Zhang, S. Dracheva, S. C. Sealfon, and M. S. Lidow (2002)
J. Neurosci. 22, 6092-6105
   Abstract »    Full Text »    PDF »
Cooperation of Protein Kinase A and Ras/ERK Signaling Pathways Is Required for AP-1-mediated Activation of Fibroblast Growth Factor-inducible Response Element (FiRE).
J.-P. Pursiheimo, J. Saari, M. Jalkanen, and M. Salmivirta (2002)
J. Biol. Chem. 277, 25344-25355
   Abstract »    Full Text »    PDF »
Striatal Enriched Phosphatase 61 Dephosphorylates Fyn at Phosphotyrosine 420.
T.-H. Nguyen, J. Liu, and P. J. Lombroso (2002)
J. Biol. Chem. 277, 24274-24279
   Abstract »    Full Text »    PDF »
ERK2 enters the nucleus by a carrier-independent mechanism.
A. W. Whitehurst, J. L. Wilsbacher, Y. You, K. Luby-Phelps, M. S. Moore, and M. H. Cobb (2002)
PNAS 99, 7496-7501
   Abstract »    Full Text »    PDF »
Heat Stress Activates the Yeast High-Osmolarity Glycerol Mitogen-Activated Protein Kinase Pathway, and Protein Tyrosine Phosphatases Are Essential under Heat Stress.
A. Winkler, C. Arkind, C. P. Mattison, A. Burkholder, K. Knoche, and I. Ota (2002)
Eukaryot. Cell 1, 163-173
   Abstract »    Full Text »    PDF »
Cross Talk between beta -Adrenergic and Bradykinin B2 Receptors Results in Cooperative Regulation of Cyclic AMP Accumulation and Mitogen-Activated Protein Kinase Activity.
S. Hanke, B. Nurnberg, D. H. Groll, and C. Liebmann (2001)
Mol. Cell. Biol. 21, 8452-8460
   Abstract »    Full Text »    PDF »
Cardioprotective Effect Afforded by Transient Exposure to Phosphodiesterase III Inhibitors: The Role of Protein Kinase A and p38 Mitogen-Activated Protein Kinase.
S. Sanada, M. Kitakaze, P. J. Papst, H. Asanuma, K. Node, S. Takashima, M. Asakura, H. Ogita, Y. Liao, Y. Sakata, et al. (2001)
Circulation 104, 705-710
   Abstract »    Full Text »    PDF »
Tyrosine-Phosphorylated Extracellular Signal-Regulated Kinase Associates with the Golgi Complex during G2/M Phase of the Cell Cycle: Evidence for Regulation of Golgi Structure.
H. Cha and P. Shapiro (2001)
J. Cell Biol. 153, 1355-1368
   Abstract »    Full Text »    PDF »
Integrin-Mediated Adhesion Regulates ERK Nuclear Translocation and Phosphorylation of Elk-1.
A. E. Aplin, S. A. Stewart, R. K. Assoian, and R.L. Juliano (2001)
J. Cell Biol. 153, 273-282
   Abstract »    Full Text »    PDF »
Simultaneous Activation of p38 MAPK and p42/44 MAPK by ATP Stimulates the K+ Current ITREK in Cardiomyocytes.
F. Aimond, J.-M. Rauzier, C. Bony, and G. Vassort (2000)
J. Biol. Chem. 275, 39110-39116
   Abstract »    Full Text »    PDF »
Evidence for Protein Kinase C-Dependent and -Independent Activation of Mitogen-Activated Protein Kinase in T Cells: Potential Role of Additional Diacylglycerol Binding Proteins.
L. G. Puente, J. C. Stone, and H. L. Ostergaard (2000)
J. Immunol. 165, 6865-6871
   Abstract »    Full Text »    PDF »
Cell-Type Specific Integration of Cross-Talk between Extracellular Signal-Regulated Kinase and cAMP Signaling.
M. D. Houslay and W. Kolch (2000)
Mol. Pharmacol. 58, 659-668
   Full Text »    PDF »
Physiological Control of Smooth Muscle-specific Gene Expression through Regulated Nuclear Translocation of Serum Response Factor.
B. Camoretti-Mercado, H.-W. Liu, A. J. Halayko, S. M. Forsythe, J. W. Kyle, B. Li, Y. Fu, J. McConville, P. Kogut, J. E. Vieira, et al. (2000)
J. Biol. Chem. 275, 30387-30393
   Abstract »    Full Text »    PDF »
The Dopamine/D1 Receptor Mediates the Phosphorylation and Inactivation of the Protein Tyrosine Phosphatase STEP via a PKA-Dependent Pathway.
S. Paul, G. L. Snyder, H. Yokakura, M. R. Picciotto, A. C. Nairn, and P. J. Lombroso (2000)
J. Neurosci. 20, 5630-5638
   Abstract »    Full Text »    PDF »
Physiological Control of Smooth Muscle-Specific Gene Expression Through Regulated Nuclear Translocation of Serum Response Factor.
B. Camoretti-Mercado, H. W. Liu, A. J. Halayko, S. M. Forsythe, J. W. Kyle, B. Li, Y. Fu, J. McConville, P. Kogut, J. E. Vieira, et al. (2000)
J. Biol. Chem.
   Abstract »
Simultaneous activation of p38MAPK and p42/44MAPK by ATP stimulate the K+ current, ITREK in cardiomyocytes.
F. Aimond, J.-M. Rauzier, C. Bony, and G. Vassort (2000)
J. Biol. Chem.
   Abstract »
A Novel MAPK Phosphatase MKP-7 Acts Preferentially on JNK/SAPK and p38alpha and beta MAPKs.
T. Tanoue, T. Yamamoto, R. Maeda, and E. Nishida (2001)
J. Biol. Chem. 276, 26629-26639
   Abstract »    Full Text »    PDF »
Two Clusters of Residues at the Docking Groove of Mitogen-activated Protein Kinases Differentially Mediate Their Functional Interaction with the Tyrosine Phosphatases PTP-SL and STEP.
C. Tarrega, C. Blanco-Aparicio, J. J. Munoz, and R. Pulido (2002)
J. Biol. Chem. 277, 2629-2636
   Abstract »    Full Text »    PDF »
Regulation of Nuclear Localization during Signaling.
M. S. Cyert (2001)
J. Biol. Chem. 276, 20805-20808
   Full Text »    PDF »
Activation of p42 Mitogen-activated Protein Kinase (MAPK), but not c-Jun NH2-Terminal Kinase, Induces Phosphorylation and Stabilization of MAPK Phosphatase XCL100 in Xenopus Oocytes.
M. L. Sohaskey and J. E. Ferrell Jr. (2002)
Mol. Biol. Cell 13, 454-468
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882