Academic journal article Genetics

Conversion of the LIN-1 ETS Protein of Caenorhabditis Elegans from a SUMOylated Transcriptional Repressor to a Phosphorylated Transcriptional Activator

Academic journal article Genetics

Conversion of the LIN-1 ETS Protein of Caenorhabditis Elegans from a SUMOylated Transcriptional Repressor to a Phosphorylated Transcriptional Activator

Article excerpt

CELL fates are established during development by spatially controlled activation of signal transduction pathways that regulate transcription factors. The Elk subfamily of ETS transcription factors are critical targets of the receptor tyrosine kinase (RTK)/Ras/extracellular-regulated kinase (ERK)-signaling pathway (Treisman 1994). This subfamily includes extensively characterized proteins from three divergent animals: vertebrate Elk-1, Drosophila Aop/Yan, and Caenorhabditis elegans LIN-1. The mechanisms that enable ETS proteins to switch cell fates in response to signaling pathway activation are not fully defined, and to address this important issue it is critical to elucidate the function of these proteins both prior to ERK activation and following phosphorylation by ERK. These issues have significant implications for human health, since ETS proteins contribute to human diseases including cancer (Dittmer 2003).

lin-1 has been extensively characterized during development of the hermaphrodite vulva, an epidermal structure used for egg laying and sperm entry (reviewed by Horvitz and Sternberg 1991; Greenwald 1997; Kornfeld 1997; Sternberg 2005; Sundaram 2013). In third-larval-stage hermaphrodites, six ventral epidermal blast cells called P3.p-P8.p (Pn.p cells) lie along the anterior-posterior axis. These Pn.p cells are an equivalence group, since each cell can adopt the 1^ vulval cell fate (eight descendants), the 2^ vulval cell fate (seven descendants), or the nonvulval 3^ cell fate (two descendants). During vulval induction, the anchor cell of the somatic gonad secretes the LIN-3 ligand, an epidermal growth f actor (EGF) homolog, thereby activating the LET-23/RTK on the adjacent P6.p cell (Aroian et al. 1990; Hill and Sternberg 1992) . Activated LET-23 recruits the SEM-5 adaptor (GRB2) and the LET-341/SOS-1 guanine nucleotide exchange factor (SOS), followed by sequential activation of the GTPase LET-60 (RAS) and the protein kinases LIN-45 (RAF), MEK-2 (MAPK kinase, or MEK), and MPK-1 (ERK) (Beitel et al. 1990; Han and Sternberg 1990; Clark et al. 1992; Han et al. 1993; Lackner et al. 1994; Wu and Han 1994; Kornfeld et al. 1995; Wu et al. 1995; Chang et al. 2000; Hsu et al. 2002). Activated MPK-1 phosphorylates substrates including the LIN-1 ETS transcription factor, thereby promoting the 1° fate in P6.p. P6.p signals P5.p and P7.p to adopt 2° fates by activating a lateral signal involving LIN-12/ Notch. The 22 descendants of P5.p, P6.p, and P7.p invaginate and differentiate to form the vulval structure. P3.p, P4.p, and P8.p receive neither signal and therefore adopt 3^ fates. Mutations that reduce activation of RTK/Ras/MAPK signaling cause a vulvaless (Vul) phenotype, whereas mutations that constitutively activate this pathway cause more than three Pn.p cells to adopt the 1° or 2° vulval cell fate, resulting in amultivulval(Muv) phenotype characterized by ectopic patches of vulval tissue.

LIN-1 is a transcription factor that plays a critical role in establishing vulval cell fates. Loss-of-function mutations that abrogate sequence-specific DNA-binding activity cause a strong Muv phenotype, demonstrating that DNA binding is necessary for lin-1 function and that lin-1 function is necessary to inhibit the 1° fate (Sulston and Horvitz 1981; Beitel et al. 1995; Miley et al. 2004). Genetic epistasis studies established that lin-1 functions downstream of mpk-1 ERK (Ferguson et al. 1987; Lackner et al. 1994; Wu and Han 1994). LIN-1 contains 17 S/TP motifs that are potential ERK phosphorylation sites and two docking sites for ERK, the D-domain and the FQFP motif (Jacobs et al. 1998, 1999; Tan et al. 1998). Mutations of LIN-1 that decrease phosphorylation by ERK cause a gain-offunction Vul phenotype, indicating that phosphorylation is necessary to stop LIN-1 from inhibiting the 1° fate (Jacobs et al. 1998). These studies are consistent with two possible models. Phosphorylation by ERK may abrogate LIN-1 activity in P6.p. Alternatively, phosphorylation may convert LIN-1 from an inhibitor to an activator of the 1° cell fate. …

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