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.

Subscribe

Logo for

Science 299 (5609): 1061-1064

Copyright © 2003 by the American Association for the Advancement of Science

Rewiring MAP Kinase Pathways Using Alternative Scaffold Assembly Mechanisms

Sang-Hyun Park, Ali Zarrinpar, Wendell A. Lim*

How scaffold proteins control information flow in signaling pathways is poorly understood: Do they simply tether components, or do they precisely orient and activate them? We found that the yeast mitogen-activated protein (MAP) kinase scaffold Ste5 is tolerant to major stereochemical perturbations; heterologous protein interactions could functionally replace native kinase recruitment interactions, indicating that simple tethering is largely sufficient for scaffold-mediated signaling. Moreover, by engineering a scaffold that tethers a unique kinase set, we could create a synthetic MAP kinase pathway with non-natural input-output properties. These findings demonstrate that scaffolds are highly flexible organizing factors that can facilitate pathway evolution and engineering.

Department of Cellular and Molecular Pharmacology and Department of Biochemistry and Biophysics, University of California, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
*   To whom correspondence should be addressed. E-mail: wlim{at}itsa.ucsf.edu



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Quantitative effect of scaffold abundance on signal propagation.
S. A. Chapman and A. R. Asthagiri (2014)
Mol Syst Biol 5, 313
   Abstract »    Full Text »    PDF »
Synthesizing a novel genetic sequential logic circuit: a push-on push-off switch.
C. Lou, X. Liu, M. Ni, Y. Huang, Q. Huang, L. Huang, L. Jiang, D. Lu, M. Wang, C. Liu, et al. (2014)
Mol Syst Biol 6, 350
   Abstract »    Full Text »    PDF »
Synthetic protein-protein interaction domains created by shuffling Cys2His2 zinc-fingers.
A. V. Giesecke, R. Fang, and J. K. Joung (2014)
Mol Syst Biol 2, 2006.0011
   Abstract »    Full Text »    PDF »
Synthetic biology: new engineering rules for an emerging discipline.
E. Andrianantoandro, S. Basu, D. K. Karig, and R. Weiss (2014)
Mol Syst Biol 2, 2006.0028
   Abstract »    Full Text »    PDF »
Scaffold State Switching Amplifies, Accelerates, and Insulates Protein Kinase C Signaling.
E. C. Greenwald, J. M. Redden, K. L. Dodge-Kafka, and J. J. Saucerman (2014)
J. Biol. Chem. 289, 2353-2360
   Abstract »    Full Text »    PDF »
Dynamically Reshaping Signaling Networks to Program Cell Fate via Genetic Controllers.
K. E. Galloway, E. Franco, and C. D. Smolke (2013)
Science 341, 1235005
   Abstract »    Full Text »    PDF »
Intramolecular arrangement of sensor and regulator overcomes relaxed specificity in hybrid two-component systems.
G. E. Townsend II, V. Raghavan, I. Zwir, and E. A. Groisman (2013)
PNAS 110, E161-E169
   Abstract »    Full Text »    PDF »
Response to Hyperosmotic Stress.
H. Saito and F. Posas (2012)
Genetics 192, 289-318
   Abstract »    Full Text »    PDF »
Wendell Lim: Exploring the path not chosen.
C. Sedwick (2012)
J. Cell Biol. 198, 956-957
   Full Text »    PDF »
Understanding Signaling Dynamics Through Synthesis.
A. L. Slusarczyk and R. Weiss (2012)
Science Signaling 5, pe16
   Abstract »    Full Text »    PDF »
DNA-guided assembly of biosynthetic pathways promotes improved catalytic efficiency.
R. J. Conrado, G. C. Wu, J. T. Boock, H. Xu, S. Y. Chen, T. Lebar, J. Turnsek, N. Tomsic, M. Avbelj, R. Gaber, et al. (2012)
Nucleic Acids Res. 40, 1879-1889
   Abstract »    Full Text »    PDF »
Modularity of a carbon-fixing protein organelle.
W. Bonacci, P. K. Teng, B. Afonso, H. Niederholtmeyer, P. Grob, P. A. Silver, and D. F. Savage (2012)
PNAS 109, 478-483
   Abstract »    Full Text »    PDF »
Synthetic Biology: Integrated Gene Circuits.
N. Nandagopal and M. B. Elowitz (2011)
Science 333, 1244-1248
   Abstract »    Full Text »    PDF »
Organization of Intracellular Reactions with Rationally Designed RNA Assemblies.
C. J. Delebecque, A. B. Lindner, P. A. Silver, and F. A. Aldaye (2011)
Science 333, 470-474
   Abstract »    Full Text »    PDF »
Recruitment interactions can override catalytic interactions in determining the functional identity of a protein kinase.
A. P. Won, J. E. Garbarino, and W. A. Lim (2011)
PNAS 108, 9809-9814
   Abstract »    Full Text »    PDF »
Scaffold Proteins: Hubs for Controlling the Flow of Cellular Information.
M. C. Good, J. G. Zalatan, and W. A. Lim (2011)
Science 332, 680-686
   Abstract »    Full Text »    PDF »
Single-Cell Analysis Reveals That Insulation Maintains Signaling Specificity Between Two Yeast MAPK Pathways with Common Components.
J. C. Patterson, E. S. Klimenko, and J. Thorner (2010)
Science Signaling 3, ra75
   Abstract »    Full Text »    PDF »
Strategies for protein synthetic biology.
R. Grunberg and L. Serrano (2010)
Nucleic Acids Res. 38, 2663-2675
   Abstract »    Full Text »    PDF »
The pmk1-like mitogen-activated protein kinase from Lecanicillium (Verticillium) fungicola is not required for virulence on Agaricus bisporus.
P. D. Collopy, R. C. Amey, M. J. Sergeant, M. P. Challen, P. R. Mills, G. D. Foster, and A. M. Bailey (2010)
Microbiology 156, 1439-1447
   Abstract »    Full Text »    PDF »
Alteration of Substrate Specificity: The Variable N-Terminal Domain of Tobacco Ca2+-Dependent Protein Kinase Is Important for Substrate Recognition.
T. Ito, M. Nakata, J. Fukazawa, S. Ishida, and Y. Takahashi (2010)
PLANT CELL 22, 1592-1604
   Abstract »    Full Text »    PDF »
Deciphering Protein Kinase Specificity Through Large-Scale Analysis of Yeast Phosphorylation Site Motifs.
J. Mok, P. M. Kim, H. Y. K. Lam, S. Piccirillo, X. Zhou, G. R. Jeschke, D. L. Sheridan, S. A. Parker, V. Desai, M. Jwa, et al. (2010)
Science Signaling 3, ra12
   Abstract »    Full Text »    PDF »
Composite RNA aptamers as functional mimics of proteins.
D. Xu and H. Shi (2009)
Nucleic Acids Res. 37, e71
   Abstract »    Full Text »    PDF »
A Tobacco Calcium-Dependent Protein Kinase, CDPK1, Regulates the Transcription Factor REPRESSION OF SHOOT GROWTH in Response to Gibberellins.
S. Ishida, T. Yuasa, M. Nakata, and Y. Takahashi (2008)
PLANT CELL 20, 3273-3288
   Abstract »    Full Text »    PDF »
Rolling out DNA nanostructures in vivo.
P. J. Paukstelis and A. D. Ellington (2008)
PNAS 105, 17593-17594
   Full Text »    PDF »
SYSTEMS BIOLOGY: Customized Signaling Circuits.
P. M. Pryciak (2008)
Science 319, 1489-1490
   Abstract »    Full Text »    PDF »
Using Engineered Scaffold Interactions to Reshape MAP Kinase Pathway Signaling Dynamics.
C. J. Bashor, N. C. Helman, S. Yan, and W. A. Lim (2008)
Science 319, 1539-1543
   Abstract »    Full Text »    PDF »
Biology by design: reduction and synthesis of cellular components and behaviour.
P. Marguet, F. Balagadde, C. Tan, and L. You (2007)
J R Soc Interface 4, 607-623
   Abstract »    Full Text »    PDF »
Scaffold proteins confer diverse regulatory properties to protein kinase cascades.
J. W. Locasale, A. S. Shaw, and A. K. Chakraborty (2007)
PNAS 104, 13307-13312
   Abstract »    Full Text »    PDF »
Designing biological systems.
D. A. Drubin, J. C. Way, and P. A. Silver (2007)
Genes & Dev. 21, 242-254
   Abstract »    Full Text »    PDF »
Interdomain Interactions in the Tumor Suppressor Discs Large Regulate Binding to the Synaptic Protein GukHolder.
Y. Qian and K. E. Prehoda (2006)
J. Biol. Chem. 281, 35757-35763
   Abstract »    Full Text »    PDF »
Synthetic biology--putting engineering into biology.
M. Heinemann and S. Panke (2006)
Bioinformatics 22, 2790-2799
   Abstract »    Full Text »    PDF »
Multiple Upstream Signals Converge on the Adaptor Protein Mst50 in Magnaporthe grisea.
G. Park, C. Xue, X. Zhao, Y. Kim, M. Orbach, and J.-R. Xu (2006)
PLANT CELL 18, 2822-2835
   Abstract »    Full Text »    PDF »
RACK1 mediates multiple hormone responsiveness and developmental processes in Arabidopsis.
J.-G. Chen, H. Ullah, B. Temple, J. Liang, J. Guo, J. M. Alonso, J. R. Ecker, and A. M. Jones (2006)
J. Exp. Bot. 57, 2697-2708
   Abstract »    Full Text »    PDF »
The Ste5 Scaffold Allosterically Modulates Signaling Output of the Yeast Mating Pathway.
R. P. Bhattacharyya, A. Remenyi, M. C. Good, C. J. Bashor, A. M. Falick, and W. A. Lim (2006)
Science 311, 822-826
   Abstract »    Full Text »    PDF »
RNA as a Flexible Scaffold for Proteins: Yeast Telomerase and Beyond.
D.C. ZAPPULLA and T.R. CECH (2006)
Cold Spring Harb Symp Quant Biol 71, 217-224
   Abstract »    PDF »
A General Model for Preferential Hetero-oligomerization of LIN-2/7 Domains: MECHANISM UNDERLYING DIRECTED ASSEMBLY OF SUPRAMOLECULAR SIGNALING COMPLEXES.
K. Y. Petrosky, H. D. Ou, F. Lohr, V. Dotsch, and W. A. Lim (2005)
J. Biol. Chem. 280, 38528-38536
   Abstract »    Full Text »    PDF »
Spontaneous evolution of modularity and network motifs.
N. Kashtan and U. Alon (2005)
PNAS 102, 13773-13778
   Abstract »    Full Text »    PDF »
IQGAP1 Is a Scaffold for Mitogen-Activated Protein Kinase Signaling.
M. Roy, Z. Li, and D. B. Sacks (2005)
Mol. Cell. Biol. 25, 7940-7952
   Abstract »    Full Text »    PDF »
Arabidopsis SENESCENCE-ASSOCIATED GENE101 Stabilizes and Signals within an ENHANCED DISEASE SUSCEPTIBILITY1 Complex in Plant Innate Immunity.
B. J. Feys, M. Wiermer, R. A. Bhat, L. J. Moisan, N. Medina-Escobar, C. Neu, A. Cabral, and J. E. Parker (2005)
PLANT CELL 17, 2601-2613
   Abstract »    Full Text »    PDF »
Role of the JIP4 Scaffold Protein in the Regulation of Mitogen-Activated Protein Kinase Signaling Pathways.
N. Kelkar, C. L. Standen, and R. J. Davis (2005)
Mol. Cell. Biol. 25, 2733-2743
   Abstract »    Full Text »    PDF »
Forcing interactions as a genetic screen to identify proteins that exert a defined activity.
M. DeVit, P. J. Cullen, M. Branson, G. F. Sprague Jr., and S. Fields (2005)
Genome Res. 15, 560-565
   Abstract »    Full Text »    PDF »
Mitogen-Activated Protein Kinases with Distinct Requirements for Ste5 Scaffolding Influence Signaling Specificity in Saccharomyces cerevisiae.
L. J. Flatauer, S. F. Zadeh, and L. Bardwell (2005)
Mol. Cell. Biol. 25, 1793-1803
   Abstract »    Full Text »    PDF »
Protein Kinases.
A. Caplan (2005)
Sci. STKE 2005, tr7
   Abstract »    Full Text »    PDF »
Counting of Rif1p and Rif2p on Saccharomyces cerevisiae Telomeres Regulates Telomere Length.
D. L. Levy and E. H. Blackburn (2004)
Mol. Cell. Biol. 24, 10857-10867
   Abstract »    Full Text »    PDF »
Persistent Activation by Constitutive Ste7 Promotes Kss1-Mediated Invasive Growth but Fails To Support Fus3-Dependent Mating in Yeast.
S. Maleri, Q. Ge, E. A. Hackett, Y. Wang, H. G. Dohlman, and B. Errede (2004)
Mol. Cell. Biol. 24, 9221-9238
   Abstract »    Full Text »    PDF »
Death-Associated Protein Kinase Phosphorylates ZIP Kinase, Forming a Unique Kinase Hierarchy To Activate Its Cell Death Functions.
G. Shani, L. Marash, D. Gozuacik, S. Bialik, L. Teitelbaum, G. Shohat, and A. Kimchi (2004)
Mol. Cell. Biol. 24, 8611-8626
   Abstract »    Full Text »    PDF »
Switching desaturase enzyme specificity by alternate subcellular targeting.
I. Heilmann, M. S. Pidkowich, T. Girke, and J. Shanklin (2004)
PNAS 101, 10266-10271
   Abstract »    Full Text »    PDF »
A Semidominant Mutation in an Arabidopsis Mitogen-Activated Protein Kinase Phosphatase-Like Gene Compromises Cortical Microtubule Organization.
K. Naoi and T. Hashimoto (2004)
PLANT CELL 16, 1841-1853
   Abstract »    Full Text »    PDF »
Scaffold Proteins in Mammalian MAP Kinase Cascades.
K. Yoshioka (2004)
J. Biochem. 135, 657-661
   Abstract »    Full Text »    PDF »
Role of the cytoskeleton in signaling networks.
G. Forgacs, S. H. Yook, P. A. Janmey, H. Jeong, and C. G. Burd (2004)
J. Cell Sci. 117, 2769-2775
   Abstract »    Full Text »    PDF »
Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists.
T. Vomastek, H.-J. Schaeffer, A. Tarcsafalvi, M. E. Smolkin, E. A. Bissonette, and M. J. Weber (2004)
PNAS 101, 6981-6986
   Abstract »    Full Text »    PDF »
2003: Signaling Breakthroughs of the Year.
E. M. Adler, N. R. Gough, and L. B. Ray (2004)
Sci. STKE 2004, eg1
   Abstract »    Full Text »    PDF »
Molecular genetic perspectives on cross-talk and specificity in abiotic stress signalling in plants.
V. Chinnusamy, K. Schumaker, and J.-K. Zhu (2004)
J. Exp. Bot. 55, 225-236
   Abstract »    Full Text »    PDF »
Phenotypic and Transcriptional Plasticity Directed by a Yeast Mitogen-Activated Protein Kinase Network.
A. Breitkreutz, L. Boucher, B.-J. Breitkreutz, M. Sultan, I. Jurisica, and M. Tyers (2003)
Genetics 165, 997-1015
   Abstract »    Full Text »    PDF »
Redirecting tyrosine kinase signaling to an apoptotic caspase pathway through chimeric adaptor proteins.
P. L. Howard, M. C. Chia, S. Del Rizzo, F.-F. Liu, and T. Pawson (2003)
PNAS 100, 11267-11272
   Abstract »    Full Text »    PDF »
Recruitment of JNK to JIP1 and JNK-dependent JIP1 Phosphorylation Regulates JNK Module Dynamics and Activation.
D. Nihalani, H. N. Wong, and L. B. Holzman (2003)
J. Biol. Chem. 278, 28694-28702
   Abstract »    Full Text »    PDF »
Convergence of Signaling Pathways Induced by Systemin, Oligosaccharide Elicitors, and Ultraviolet-B Radiation at the Level of Mitogen-Activated Protein Kinases in Lycopersicon peruvianum Suspension-Cultured Cells.
S. R. Holley, R. D. Yalamanchili, D. S. Moura, C. A. Ryan, and J. W. Stratmann (2003)
Plant Physiology 132, 1728-1738
   Abstract »    Full Text »    PDF »
Assembly of Cell Regulatory Systems Through Protein Interaction Domains.
T. Pawson and P. Nash (2003)
Science 300, 445-452
   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