Gain-of-Function Mutations in the Caenorhabditis elegans lin-1 ETS Gene Identify a C-Terminal Regulatory Domain Phosphorylated by ERK MAP Kinase

Corresponding author: Kerry Kornfeld, Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Campus Box 8103, 660 S. Euclid Ave., St. Louis, MO 63110., kornfeld{at}pharmdec.wustl.edu (E-mail).

Communicating editor: I. GREENWALD

Genetic analysis of lin-1 loss-of-function mutations suggests that lin-1 controls multiple cell-fate decisions during Caenorhabditis elegans development and is negatively regulated by a conserved receptor tyrosine kinase-Ras-ERK mitogen-activated protein (MAP) kinase signal transduction pathway. LIN-1 protein contains an ETS domain and presumably regulates transcription. We identified and characterized six gain-of-function mutations that define a new class of lin-1 allele. These lin-1 alleles appeared to be constitutively active and unresponsive to negative regulation. Each allele has a single-base change that affects the predicted C terminus of LIN-1, suggesting this region is required for negative regulation. The C terminus of LIN-1 was a high-affinity substrate for Erk2 in vitro, suggesting that LIN-1 is directly regulated by ERK MAP kinase. Because mpk-1 ERK MAP kinase controls at least one cell-fate decision that does not require lin-1, our results suggest that MPK-1 contributes to the specificity of this receptor tyrosine kinase-Ras-MAP kinase signal transduction pathway by phosphorylating different proteins in different developmental contexts. These lin-1 mutations all affect a four-amino-acid motif, FQFP, that is conserved in vertebrate and Drosophila ETS proteins that are also phosphorylated by ERK MAP kinase. This sequence may be a substrate recognition motif for the ERK subfamily of MAP kinases.

This article has been cited by other articles:

				O. Kaidanovich-Beilin and H. Eldar-Finkelman Peptides Targeting Protein Kinases: Strategies and Implications. Physiology, December 1, 2006; 21(6): 411 - 418. [Abstract] [Full Text] [PDF]

				B. P. Gupta, J. Liu, B. J. Hwang, N. Moghal, and P. W. Sternberg sli-3 Negatively Regulates the LET-23/Epidermal Growth Factor Receptor-Mediated Vulval Induction Pathway in Caenorhabditis elegans Genetics, November 1, 2006; 174(3): 1315 - 1326. [Abstract] [Full Text] [PDF]

				S. Polychronopoulos, M. Verykokakis, M. N. Yazicioglu, M. Sakarellos-Daitsiotis, M. H. Cobb, and G. Mavrothalassitis The Transcriptional ETS2 Repressor Factor Associates with Active and Inactive Erks through Distinct FXF Motifs J. Biol. Chem., September 1, 2006; 281(35): 25601 - 25611. [Abstract] [Full Text] [PDF]

				Y.-W. Lin and J.-L. Yang Cooperation of ERK and SCFSkp2 for MKP-1 Destruction Provides a Positive Feedback Regulation of Proliferating Signaling J. Biol. Chem., January 13, 2006; 281(2): 915 - 926. [Abstract] [Full Text] [PDF]

				D. J. Eastburn and M. Han A Gain-of-Function Allele of cbp-1, the Caenorhabditis elegans Ortholog of the Mammalian CBP/p300 Gene, Causes an Increase in Histone Acetyltransferase Activity and Antagonism of Activated Ras Mol. Cell. Biol., November 1, 2005; 25(21): 9427 - 9434. [Abstract] [Full Text] [PDF]

				M. V. Sundaram The love-hate relationship between Ras and Notch Genes & Dev., August 15, 2005; 19(16): 1825 - 1839. [Abstract] [Full Text] [PDF]

				E. R. Leight, D. Glossip, and K. Kornfeld Sumoylation of LIN-1 promotes transcriptional repression and inhibition of vulval cell fates Development, March 1, 2005; 132(5): 1047 - 1056. [Abstract] [Full Text] [PDF]

				G. R. Miley, D. Fantz, D. Glossip, X. Lu, R. M. Saito, R. E. Palmer, T. Inoue, S. van den Heuvel, P. W. Sternberg, and K. Kornfeld Identification of Residues of the Caenorhabditis elegans LIN-1 ETS Domain That Are Necessary for DNA Binding and Regulation of Vulval Cell Fates Genetics, August 1, 2004; 167(4): 1697 - 1709. [Abstract] [Full Text] [PDF]

				P. P. Roux and J. Blenis ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions Microbiol. Mol. Biol. Rev., June 1, 2004; 68(2): 320 - 344. [Abstract] [Full Text] [PDF]

				A. W. Whitehurst, F. L. Robinson, M. S. Moore, and M. H. Cobb The Death Effector Domain Protein PEA-15 Prevents Nuclear Entry of ERK2 by Inhibiting Required Interactions J. Biol. Chem., March 26, 2004; 279(13): 12840 - 12847. [Abstract] [Full Text] [PDF]

				Y. Shibata, R. Branicky, I. O. Landaverde, and S. Hekimi Redox Regulation of Germline and Vulval Development in Caenorhabditis elegans Science, December 5, 2003; 302(5651): 1779 - 1782. [Abstract] [Full Text] [PDF]

				R. M. Howard and M. V. Sundaram C. elegans EOR-1/PLZF and EOR-2 positively regulate Ras and Wnt signaling and function redundantly with LIN-25 and the SUR-2 Mediator component Genes & Dev., July 15, 2002; 16(14): 1815 - 1827. [Abstract] [Full Text] [PDF]

				C. E. Rocheleau, R. M. Howard, A. P. Goldman, M. L. Volk, L. J. Girard, and M. V. Sundaram A lin-45 raf Enhancer Screen Identifies eor-1, eor-2 and Unusual Alleles of Ras Pathway Genes in Caenorhabditis elegans Genetics, May 1, 2002; 161(1): 121 - 131. [Abstract] [Full Text] [PDF]

				V. Hsu, C. L. Zobel, E. J. Lambie, T. Schedl, and K. Kornfeld Caenorhabditis elegans lin-45 raf Is Essential for Larval Viability, Fertility and the Induction of Vulval Cell Fates Genetics, February 1, 2002; 160(2): 481 - 492. [Abstract] [Full Text] [PDF]

				L. Nilsson, T. Tiensuu, and S. Tuck Caenorhabditis elegans lin-25: A Study of Its Role in Multiple Cell Fate Specification Events Involving Ras and the Identification and Characterization of Evolutionarily Conserved Domains Genetics, November 1, 2000; 156(3): 1083 - 1096. [Abstract] [Full Text]

				D. M. Eisenmann and S. K. Kim Protruding Vulva Mutants Identify Novel Loci and Wnt Signaling Factors That Function During Caenorhabditis elegans Vulva Development Genetics, November 1, 2000; 156(3): 1097 - 1116. [Abstract] [Full Text]

				J. Jakubowski and K. Kornfeld A Local, High-Density, Single-Nucleotide Polymorphism Map Used to Clone Caenorhabditis elegans cdf-1 Genetics, October 1, 1999; 153(2): 743 - 752. [Abstract] [Full Text] [PDF]

				D. S. Sieburth, M. Sundaram, R. M. Howard, and M. Han A PP2A regulatory subunit positively regulates Ras-mediated signaling during Caenorhabditis elegans vulval induction Genes & Dev., October 1, 1999; 13(19): 2562 - 2569. [Abstract] [Full Text]

				D. Jacobs, D. Glossip, H. Xing, A. J. Muslin, and K. Kornfeld Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase Genes & Dev., January 15, 1999; 13(2): 163 - 175. [Abstract] [Full Text]

				L Nilsson, X Li, T Tiensuu, R Auty, I Greenwald, and S Tuck Caenorhabditis elegans lin-25: cellular focus, protein expression and requirement for sur-2 during induction of vulval fates Development, January 12, 1998; 125(23): 4809 - 4819. [Abstract] [PDF]

				D. A. Fantz, D. Jacobs, D. Glossip, and K. Kornfeld Docking Sites on Substrate Proteins Direct Extracellular Signal-regulated Kinase to Phosphorylate Specific Residues J. Biol. Chem., July 13, 2001; 276(29): 27256 - 27265. [Abstract] [Full Text] [PDF]