Multiple Functions of let-23, a Caenorhabditis elegans Receptor Tyrosine Kinase Gene Required for Vulval Induction

INVESTIGATIONS

Multiple Functions of let-23, a Caenorhabditis elegans Receptor Tyrosine Kinase Gene Required for Vulval Induction

R. V. Aroian and P. W. Sternberg
Howard Hughes Medical Institute, Division of Biology, California Institute of Technology, Pasadena, California 91125

The let-23 gene, which encodes a putative tyrosine kinase of the epidermal growth factor (EGF) receptor subfamily, has multiple functions during Caenorhabditis elegans development. We show that let-23 function is required for vulval precursor cells (VPCs) to respond to the signal that induces vulval differentiation: a complete loss of let-23 function results in no induction. However, some let-23 mutations that genetically reduce but do not eliminate let-23 function result in VPCs apparently hypersensitive to inductive signal: as many as five of six VPCs can adopt vulval fates, in contrast to the three that normally do. These results suggest that the let-23 receptor tyrosine kinase controls two opposing pathways, one that stimulates vulval differentiation and another that negatively regulates vulval differentiation. Furthermore, analysis of 16 new let-23 mutations indicates that the let-23 kinase functions in at least five tissues. Since various let-23 mutant phenotypes can be obtained independently, the let-23 gene is likely to have tissue-specific functions.

This article has been cited by other articles:

J. Milloz, F. Duveau, I. Nuez, and M.-A. Felix
Intraspecific evolution of the intercellular signaling network underlying a robust developmental system
Genes & Dev., November 1, 2008; 22(21): 3064 - 3075.
[Abstract] [Full Text] [PDF]

K. Modzelewska, M. G. Elgort, J. Huang, G. Jongeward, A. Lauritzen, C. H. Yoon, P. W. Sternberg, and N. Moghal
An Activating Mutation in sos-1 Identifies Its Dbl Domain as a Critical Inhibitor of the Epidermal Growth Factor Receptor Pathway during Caenorhabditis elegans Vulval Development
Mol. Cell. Biol., May 15, 2007; 27(10): 3695 - 3707.
[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]

C. J. Ceol, F. Stegmeier, M. M. Harrison, and H. R. Horvitz
Identification and Classification of Genes That Act Antagonistically to let-60 Ras Signaling in Caenorhabditis elegans Vulval Development
Genetics, June 1, 2006; 173(2): 709 - 726.
[Abstract] [Full Text] [PDF]

P. W. Sternberg
Pathway to RAS.
Genetics, February 1, 2006; 172(2): 727 - 731.
[Full Text] [PDF]

J. Yochem, L. R. Bell, and R. K. Herman
The Identities of sym-2, sym-3 and sym-4, Three Genes That Are Synthetically Lethal With mec-8 in Caenorhabditis elegans
Genetics, November 1, 2004; 168(3): 1293 - 1306.
[Abstract] [Full Text] [PDF]

N. Moghal, L. R. Garcia, L. A. Khan, K. Iwasaki, and P. W. Sternberg
Modulation of EGF receptor-mediated vulva development by the heterotrimeric G-protein G{alpha}q and excitable cells in C. elegans
Development, October 1, 2003; 130(19): 4553 - 4566.
[Abstract] [Full Text] [PDF]

J. H. Thomas, C. J. Ceol, H. T. Schwartz, and H. R. Horvitz
New Genes That Interact With lin-35 Rb to Negatively Regulate the let-60 ras Pathway in Caenorhabditis elegans
Genetics, May 1, 2003; 164(1): 135 - 151.
[Abstract] [Full Text] [PDF]

N. Moghal and P. W. Sternberg
A component of the transcriptional mediator complex inhibits RAS-dependent vulval fate specification in C. elegans
Development, January 1, 2003; 130(1): 57 - 69.
[Abstract] [Full Text] [PDF]

N. J. Szewczyk, B. K. Peterson, and L. A. Jacobson
Activation of Ras and the Mitogen-Activated Protein Kinase Pathway Promotes Protein Degradation in Muscle Cells of Caenorhabditis elegans
Mol. Cell. Biol., June 15, 2002; 22(12): 4181 - 4188.
[Abstract] [Full Text] [PDF]

J. E. Gleason, H. C. Korswagen, and D. M. Eisenmann
Activation of Wnt signaling bypasses the requirement for RTK/Ras signaling during C. elegans vulval induction
Genes & Dev., May 15, 2002; 16(10): 1281 - 1290.
[Abstract] [Full Text] [PDF]

Y. K. Bui and P. W. Sternberg
Caenorhabditis elegans Inositol 5-Phosphatase Homolog Negatively Regulates Inositol 1,4,5-Triphosphate Signaling in Ovulation
Mol. Biol. Cell, May 1, 2002; 13(5): 1641 - 1651.
[Abstract] [Full Text] [PDF]

J. M. Simon and P. W. Sternberg
Evidence of a mate-finding cue in the hermaphrodite nematode Caenorhabditis elegans
PNAS, January 24, 2002; (2002) 32225799.
[Abstract] [Full Text] [PDF]

C. H. Yoon, C. Chang, N. A. Hopper, G. M. Lesa, and P. W. Sternberg
Requirements of Multiple Domains of SLI-1, a Caenorhabditis elegans Homologue of c-Cbl, and an Inhibitory Tyrosine in LET-23 in Regulating Vulval Differentiation
Mol. Biol. Cell, November 1, 2000; 11(11): 4019 - 4031.
[Abstract] [Full Text]

J. Thomas and H. Horvitz
The C. elegans gene lin-36 acts cell autonomously in the lin-35 Rb pathway
Development, January 8, 1999; 126(15): 3449 - 3459.
[Abstract] [PDF]

M. J. Gutch, A. J. Flint, J. Keller, N. K. Tonks, and M. O. Hengartner
The Caenorhabditis elegans SH2 domain-containing protein tyrosine phosphatase PTP-2 participates in signal transduction during oogenesis and vulval development
Genes & Dev., February 15, 1998; 12(4): 571 - 585.
[Abstract] [Full Text]

D. Eisenmann, J. Maloof, J. Simske, C Kenyon, and S. Kim
The beta-catenin homolog BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development
Development, January 9, 1998; 125(18): 3667 - 3680.
[Abstract] [PDF]

D Levitan and I Greenwald
LIN-12 protein expression and localization during vulval development in C. elegans
Development, January 8, 1998; 125(16): 3101 - 3109.
[Abstract] [PDF]

L. Jiang and P. Sternberg
Interactions of EGF, Wnt and HOM-C genes specify the P12 neuroectoblast fate in C. elegans
Development, January 6, 1998; 125(12): 2337 - 2347.
[Abstract] [PDF]

R. Burdine, C. Branda, and M. Stern
EGL-17(FGF) expression coordinates the attraction of the migrating sex myoblasts with vulval induction in C. elegans
Development, January 3, 1998; 125(6): 1083 - 1093.
[Abstract] [PDF]

J. Maloof and C Kenyon
The Hox gene lin-39 is required during C. elegans vulval induction to select the outcome of Ras signaling
Development, January 1, 1998; 125(2): 181 - 190.
[Abstract] [PDF]

A. Hajnal, C. W. Whitfield, and S. K. Kim
Inhibition of Caenorhabditis elegans vulval induction by gap-1 and by let-23 receptor tyrosine kinase
Genes & Dev., October 15, 1997; 11(20): 2715 - 2728.
[Abstract] [Full Text] [PDF]

M Sundaram, J Yochem, and M Han
A Ras-mediated signal transduction pathway is involved in the control of sex myoblast migration in Caenorhabditis elegans
Development, January 9, 1996; 122(9): 2823 - 2833.
[Abstract] [PDF]

R Hoskins, A. Hajnal, S. Harp, and S. Kim
The C. elegans vulval induction gene lin-2 encodes a member of the MAGUK family of cell junction proteins
Development, January 1, 1996; 122(1): 97 - 111.
[Abstract] [PDF]

G J Beitel, S Tuck, I Greenwald, and H R Horvitz
The Caenorhabditis elegans gene lin-1 encodes an ETS-domain protein and defines a branch of the vulval induction pathway.
Genes & Dev., December 15, 1995; 9(24): 3149 - 3162.
[Abstract] [PDF]

N Singh and M Han
sur-2, a novel gene, functions late in the let-60 ras-mediated signaling pathway during Caenorhabditis elegans vulval induction.
Genes & Dev., September 15, 1995; 9(18): 2251 - 2265.
[Abstract] [PDF]

C. Yoon, J Lee, G. Jongeward, and P. Sternberg
Similarity of sli-1, a regulator of vulval development in C. elegans, to the mammalian proto-oncogene c-cbl
Science, August 25, 1995; 269(5227): 1102 - 1105.
[Abstract] [PDF]

Y Wu, M Han, and K L Guan
MEK-2, a Caenorhabditis elegans MAP kinase kinase, functions in Ras-mediated vulval induction and other developmental events.
Genes & Dev., March 15, 1995; 9(6): 742 - 755.
[Abstract] [PDF]

K Kornfeld, K L Guan, and H R Horvitz
The Caenorhabditis elegans gene mek-2 is required for vulval induction and encodes a protein similar to the protein kinase MEK.
Genes & Dev., March 15, 1995; 9(6): 756 - 768.
[Abstract] [PDF]

D. Church, K. Guan, and E. Lambie
Three genes of the MAP kinase cascade, mek-2, mpk-1/sur-1 and let-60 ras, are required for meiotic cell cycle progression in Caenorhabditis elegans
Development, January 8, 1995; 121(8): 2525 - 2535.
[Abstract] [PDF]

M Koga and Y Ohshima
Mosaic analysis of the let-23 gene function in vulval induction of Caenorhabditis elegans
Development, January 8, 1995; 121(8): 2655 - 2666.
[Abstract] [PDF]

A. Newman, J. White, and P. Sternberg
The Caenorhabditis elegans lin-12 gene mediates induction of ventral uterine specialization by the anchor cell
Development, January 2, 1995; 121(2): 263 - 271.
[Abstract] [PDF]

M. A. Sturtevant, J. W. O'Neill, and E. Bier
Down-regulation of Drosophila Egf-r mRNA levels following hyperactivated receptor signaling
Development, September 1, 1994; 120(9): 2593 - 2600.
[Abstract] [PDF]

Y Wu and M Han
Suppression of activated Let-60 ras protein defines a role of Caenorhabditis elegans Sur-1 MAP kinase in vulval differentiation.
Genes & Dev., January 15, 1994; 8(2): 147 - 159.
[Abstract] [PDF]

M R Lackner, K Kornfeld, L M Miller, H R Horvitz, and S K Kim
A MAP kinase homolog, mpk-1, is involved in ras-mediated induction of vulval cell fates in Caenorhabditis elegans.
Genes & Dev., January 15, 1994; 8(2): 160 - 173.
[Abstract] [PDF]

H. Chamberlin and P. Sternberg
The lin-3/let-23 pathway mediates inductive signalling during male spicule development in Caenorhabditis elegans
Development, January 10, 1994; 120(10): 2713 - 2721.
[Abstract] [PDF]

M. Herman and H. Horvitz
The Caenorhabditis elegans gene lin-44 controls the polarity of asymmetric cell divisions
Development, January 5, 1994; 120(5): 1035 - 1047.
[Abstract] [PDF]

J Austin and C Kenyon
Cell contact regulates neuroblast formation in the Caenorhabditis elegans lateral epidermis
Development, January 2, 1994; 120(2): 313 - 323.
[Abstract] [PDF]

P.W. Sternberg, C.H. Yoon, J. Lee, G.D. Jongeward, P.S. Kayne, W.S. Katz, G. Lesa, J. Liu, A. Golden, L.S. Huang, et al.
Molecular Genetics of Proto-oncogenes and Candidate Tumor Suppressors in Caenorhabditis elegans
Cold Spring Harb Symp Quant Biol, January 1, 1994; 59(0): 155 - 163.
[Abstract] [PDF]

J Lee, G D Jongeward, and P W Sternberg
unc-101, a gene required for many aspects of Caenorhabditis elegans development and behavior, encodes a clathrin-associated protein.
Genes & Dev., January 1, 1994; 8(1): 60 - 73.
[Abstract] [PDF]

L Tessarollo, P Tsoulfas, D Martin-Zanca, D. Gilbert, N. Jenkins, N. Copeland, and L. Parada
trkC, a receptor for neurotrophin-3, is widely expressed in the developing nervous system and in non-neuronal tissues
Development, January 6, 1993; 118(2): 463 - 475.
[Abstract] [PDF]

P.W. Sternberg, R.J. Hill, G. Jongeward, L.S. Huang, and L. Carta
Intercellular Signaling during Caenorhabditis elegans Vulval Induction
Cold Spring Harb Symp Quant Biol, January 1, 1992; 57(0): 353 - 362.
[Abstract] [PDF]

S.G. Clark, M.J. Stern, and H.R. Horvitz
Genes Involved in Two Caenorhabditis elegans Cell-signaling Pathways
Cold Spring Harb Symp Quant Biol, January 1, 1992; 57(0): 363 - 373.
[Abstract] [PDF]

J. M. Simon and P. W. Sternberg
Evidence of a mate-finding cue in the hermaphrodite nematode Caenorhabditis elegans
PNAS, February 5, 2002; 99(3): 1598 - 1603.
[Abstract] [Full Text] [PDF]

				K. Modzelewska, M. G. Elgort, J. Huang, G. Jongeward, A. Lauritzen, C. H. Yoon, P. W. Sternberg, and N. Moghal An Activating Mutation in sos-1 Identifies Its Dbl Domain as a Critical Inhibitor of the Epidermal Growth Factor Receptor Pathway during Caenorhabditis elegans Vulval Development Mol. Cell. Biol., May 15, 2007; 27(10): 3695 - 3707. [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]

				C. J. Ceol, F. Stegmeier, M. M. Harrison, and H. R. Horvitz Identification and Classification of Genes That Act Antagonistically to let-60 Ras Signaling in Caenorhabditis elegans Vulval Development Genetics, June 1, 2006; 173(2): 709 - 726. [Abstract] [Full Text] [PDF]

				P. W. Sternberg Pathway to RAS. Genetics, February 1, 2006; 172(2): 727 - 731. [Full Text] [PDF]

				J. Yochem, L. R. Bell, and R. K. Herman The Identities of sym-2, sym-3 and sym-4, Three Genes That Are Synthetically Lethal With mec-8 in Caenorhabditis elegans Genetics, November 1, 2004; 168(3): 1293 - 1306. [Abstract] [Full Text] [PDF]

				N. Moghal, L. R. Garcia, L. A. Khan, K. Iwasaki, and P. W. Sternberg Modulation of EGF receptor-mediated vulva development by the heterotrimeric G-protein G{alpha}q and excitable cells in C. elegans Development, October 1, 2003; 130(19): 4553 - 4566. [Abstract] [Full Text] [PDF]

				J. H. Thomas, C. J. Ceol, H. T. Schwartz, and H. R. Horvitz New Genes That Interact With lin-35 Rb to Negatively Regulate the let-60 ras Pathway in Caenorhabditis elegans Genetics, May 1, 2003; 164(1): 135 - 151. [Abstract] [Full Text] [PDF]

				N. Moghal and P. W. Sternberg A component of the transcriptional mediator complex inhibits RAS-dependent vulval fate specification in C. elegans Development, January 1, 2003; 130(1): 57 - 69. [Abstract] [Full Text] [PDF]

				N. J. Szewczyk, B. K. Peterson, and L. A. Jacobson Activation of Ras and the Mitogen-Activated Protein Kinase Pathway Promotes Protein Degradation in Muscle Cells of Caenorhabditis elegans Mol. Cell. Biol., June 15, 2002; 22(12): 4181 - 4188. [Abstract] [Full Text] [PDF]

				J. E. Gleason, H. C. Korswagen, and D. M. Eisenmann Activation of Wnt signaling bypasses the requirement for RTK/Ras signaling during C. elegans vulval induction Genes & Dev., May 15, 2002; 16(10): 1281 - 1290. [Abstract] [Full Text] [PDF]

				Y. K. Bui and P. W. Sternberg Caenorhabditis elegans Inositol 5-Phosphatase Homolog Negatively Regulates Inositol 1,4,5-Triphosphate Signaling in Ovulation Mol. Biol. Cell, May 1, 2002; 13(5): 1641 - 1651. [Abstract] [Full Text] [PDF]

				J. M. Simon and P. W. Sternberg Evidence of a mate-finding cue in the hermaphrodite nematode Caenorhabditis elegans PNAS, January 24, 2002; (2002) 32225799. [Abstract] [Full Text] [PDF]

				C. H. Yoon, C. Chang, N. A. Hopper, G. M. Lesa, and P. W. Sternberg Requirements of Multiple Domains of SLI-1, a Caenorhabditis elegans Homologue of c-Cbl, and an Inhibitory Tyrosine in LET-23 in Regulating Vulval Differentiation Mol. Biol. Cell, November 1, 2000; 11(11): 4019 - 4031. [Abstract] [Full Text]

				J. Thomas and H. Horvitz The C. elegans gene lin-36 acts cell autonomously in the lin-35 Rb pathway Development, January 8, 1999; 126(15): 3449 - 3459. [Abstract] [PDF]

				M. J. Gutch, A. J. Flint, J. Keller, N. K. Tonks, and M. O. Hengartner The Caenorhabditis elegans SH2 domain-containing protein tyrosine phosphatase PTP-2 participates in signal transduction during oogenesis and vulval development Genes & Dev., February 15, 1998; 12(4): 571 - 585. [Abstract] [Full Text]

				D. Eisenmann, J. Maloof, J. Simske, C Kenyon, and S. Kim The beta-catenin homolog BAR-1 and LET-60 Ras coordinately regulate the Hox gene lin-39 during Caenorhabditis elegans vulval development Development, January 9, 1998; 125(18): 3667 - 3680. [Abstract] [PDF]

				D Levitan and I Greenwald LIN-12 protein expression and localization during vulval development in C. elegans Development, January 8, 1998; 125(16): 3101 - 3109. [Abstract] [PDF]

				L. Jiang and P. Sternberg Interactions of EGF, Wnt and HOM-C genes specify the P12 neuroectoblast fate in C. elegans Development, January 6, 1998; 125(12): 2337 - 2347. [Abstract] [PDF]

				R. Burdine, C. Branda, and M. Stern EGL-17(FGF) expression coordinates the attraction of the migrating sex myoblasts with vulval induction in C. elegans Development, January 3, 1998; 125(6): 1083 - 1093. [Abstract] [PDF]

				J. Maloof and C Kenyon The Hox gene lin-39 is required during C. elegans vulval induction to select the outcome of Ras signaling Development, January 1, 1998; 125(2): 181 - 190. [Abstract] [PDF]

				A. Hajnal, C. W. Whitfield, and S. K. Kim Inhibition of Caenorhabditis elegans vulval induction by gap-1 and by let-23 receptor tyrosine kinase Genes & Dev., October 15, 1997; 11(20): 2715 - 2728. [Abstract] [Full Text] [PDF]

				M Sundaram, J Yochem, and M Han A Ras-mediated signal transduction pathway is involved in the control of sex myoblast migration in Caenorhabditis elegans Development, January 9, 1996; 122(9): 2823 - 2833. [Abstract] [PDF]

				R Hoskins, A. Hajnal, S. Harp, and S. Kim The C. elegans vulval induction gene lin-2 encodes a member of the MAGUK family of cell junction proteins Development, January 1, 1996; 122(1): 97 - 111. [Abstract] [PDF]

				G J Beitel, S Tuck, I Greenwald, and H R Horvitz The Caenorhabditis elegans gene lin-1 encodes an ETS-domain protein and defines a branch of the vulval induction pathway. Genes & Dev., December 15, 1995; 9(24): 3149 - 3162. [Abstract] [PDF]

				N Singh and M Han sur-2, a novel gene, functions late in the let-60 ras-mediated signaling pathway during Caenorhabditis elegans vulval induction. Genes & Dev., September 15, 1995; 9(18): 2251 - 2265. [Abstract] [PDF]

				C. Yoon, J Lee, G. Jongeward, and P. Sternberg Similarity of sli-1, a regulator of vulval development in C. elegans, to the mammalian proto-oncogene c-cbl Science, August 25, 1995; 269(5227): 1102 - 1105. [Abstract] [PDF]

				Y Wu, M Han, and K L Guan MEK-2, a Caenorhabditis elegans MAP kinase kinase, functions in Ras-mediated vulval induction and other developmental events. Genes & Dev., March 15, 1995; 9(6): 742 - 755. [Abstract] [PDF]

				K Kornfeld, K L Guan, and H R Horvitz The Caenorhabditis elegans gene mek-2 is required for vulval induction and encodes a protein similar to the protein kinase MEK. Genes & Dev., March 15, 1995; 9(6): 756 - 768. [Abstract] [PDF]

				D. Church, K. Guan, and E. Lambie Three genes of the MAP kinase cascade, mek-2, mpk-1/sur-1 and let-60 ras, are required for meiotic cell cycle progression in Caenorhabditis elegans Development, January 8, 1995; 121(8): 2525 - 2535. [Abstract] [PDF]

				M Koga and Y Ohshima Mosaic analysis of the let-23 gene function in vulval induction of Caenorhabditis elegans Development, January 8, 1995; 121(8): 2655 - 2666. [Abstract] [PDF]