Ral Signals Through a MAP4 Kinase-p38 MAP Kinase Cascade in C. elegans Cell Fate Patterning

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Sep 6

PMID 30184501

Citations 14

Authors

Hanna Shin

Rebecca E W Kaplan

Tam Duong

Razan Fakieh

David J Reiner

Affiliations

Soon will be listed here.

Abstract

C. elegans vulval precursor cell (VPC) fates are patterned by an epidermal growth factor (EGF) gradient. High-dose EGF induces 1° VPC fate, and lower dose EGF contributes to 2° fate in support of LIN-12/Notch. We previously showed that the EGF 2°-promoting signal is mediated by LET-60/Ras switching effectors, from the canonical Raf-MEK-ERK mitogen-activated protein (MAP) kinase cascade that promotes 1° fate to the non-canonical RalGEF-Ral that promotes 2° fate. Of oncogenic Ras effectors, RalGEF-Ral is by far the least well understood. We use genetic analysis to identify an effector cascade downstream of C. elegans RAL-1/Ral, starting with an established Ral binding partner, Exo84 of the exocyst complex. Additionally, RAL-1 signals through GCK-2, a citron-N-terminal-homology-domain-containing MAP4 kinase, and PMK-1/p38 MAP kinase cascade to promote 2° fate. Our study delineates a Ral-dependent developmental signaling cascade in vivo, thus providing the mechanism by which lower EGF dose is transduced.

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References

Zand T, Reiner D, Der C . Ras effector switching promotes divergent cell fates in C. elegans vulval patterning. Dev Cell. 2011; 20(1):84-96. PMC: 3028984. DOI: 10.1016/j.devcel.2010.12.004. View

Lenormand P, Sardet C, Pages G, LAllemain G, Brunet A, Pouyssegur J . Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. J Cell Biol. 1993; 122(5):1079-88. PMC: 2119624. DOI: 10.1083/jcb.122.5.1079. View

Simske J, Kim S . Sequential signalling during Caenorhabditis elegans vulval induction. Nature. 1995; 375(6527):142-6. DOI: 10.1038/375142a0. View

Berset T, Hoier E, Battu G, Canevascini S, Hajnal A . Notch inhibition of RAS signaling through MAP kinase phosphatase LIP-1 during C. elegans vulval development. Science. 2001; 291(5506):1055-8. DOI: 10.1126/science.1055642. View

Delpire E . The mammalian family of sterile 20p-like protein kinases. Pflugers Arch. 2009; 458(5):953-67. DOI: 10.1007/s00424-009-0674-y. View

Cui M, Chen J, Myers T, Hwang B, Sternberg P, Greenwald I . SynMuv genes redundantly inhibit lin-3/EGF expression to prevent inappropriate vulval induction in C. elegans. Dev Cell. 2006; 10(5):667-72. DOI: 10.1016/j.devcel.2006.04.001. View

Timmons L, Fire A . Specific interference by ingested dsRNA. Nature. 1998; 395(6705):854. DOI: 10.1038/27579. View

Issaq S, Lim K, Counter C . Sec5 and Exo84 foster oncogenic ras-mediated tumorigenesis. Mol Cancer Res. 2010; 8(2):223-31. PMC: 2824780. DOI: 10.1158/1541-7786.MCR-09-0189. View

Kashatus D . Ral GTPases in tumorigenesis: emerging from the shadows. Exp Cell Res. 2013; 319(15):2337-42. PMC: 4270277. DOI: 10.1016/j.yexcr.2013.06.020. View

10.

Chen N, Greenwald I . The lateral signal for LIN-12/Notch in C. elegans vulval development comprises redundant secreted and transmembrane DSL proteins. Dev Cell. 2004; 6(2):183-92. DOI: 10.1016/s1534-5807(04)00021-8. View

11.

Corl A, Berger K, Ophir-Shohat G, Gesch J, Simms J, Bartlett S . Happyhour, a Ste20 family kinase, implicates EGFR signaling in ethanol-induced behaviors. Cell. 2009; 137(5):949-60. DOI: 10.1016/j.cell.2009.03.020. View

12.

Fay D, Yochem J . The SynMuv genes of Caenorhabditis elegans in vulval development and beyond. Dev Biol. 2007; 306(1):1-9. PMC: 1955466. DOI: 10.1016/j.ydbio.2007.03.016. View

13.

Jin R, Junutula J, Matern H, Ervin K, Scheller R, Brunger A . Exo84 and Sec5 are competitive regulatory Sec6/8 effectors to the RalA GTPase. EMBO J. 2005; 24(12):2064-74. PMC: 1150893. DOI: 10.1038/sj.emboj.7600699. View

14.

Dickinson D, Pani A, Heppert J, Higgins C, Goldstein B . Streamlined Genome Engineering with a Self-Excising Drug Selection Cassette. Genetics. 2015; 200(4):1035-49. PMC: 4574250. DOI: 10.1534/genetics.115.178335. View

15.

Wu B, Guo W . The Exocyst at a Glance. J Cell Sci. 2015; 128(16):2957-64. PMC: 4541039. DOI: 10.1242/jcs.156398. View

16.

Koga M, Ohshima Y . Mosaic analysis of the let-23 gene function in vulval induction of Caenorhabditis elegans. Development. 1995; 121(8):2655-66. DOI: 10.1242/dev.121.8.2655. View

17.

Papke B, Der C . Drugging RAS: Know the enemy. Science. 2017; 355(6330):1158-1163. DOI: 10.1126/science.aam7622. View

18.

Katz W, Hill R, Clandinin T, Sternberg P . Different levels of the C. elegans growth factor LIN-3 promote distinct vulval precursor fates. Cell. 1995; 82(2):297-307. DOI: 10.1016/0092-8674(95)90317-8. View

19.

Komatsu N, Aoki K, Yamada M, Yukinaga H, Fujita Y, Kamioka Y . Development of an optimized backbone of FRET biosensors for kinases and GTPases. Mol Biol Cell. 2011; 22(23):4647-56. PMC: 3226481. DOI: 10.1091/mbc.E11-01-0072. View

20.

Green J, Inoue T, Sternberg P . Opposing Wnt pathways orient cell polarity during organogenesis. Cell. 2008; 134(4):646-56. PMC: 2603076. DOI: 10.1016/j.cell.2008.06.026. View