Phosphorylation of groucho mediates RTK feedback inhibition and prolonged pathway target gene expression

Aharon Helman, Einat Cinnamon, Sharon Mezuman, Zvi Hayouka, Tonia Von Ohlen, Amir Orian, Gerardo Jiménez, Ze'Ev Paroush*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Background: Signaling by receptor tyrosine kinase (RTK) pathways plays fundamental roles in processes of cell-fate determination, often through the induction of specific transcriptional responses. Yet it is not fully understood how continuous target gene expression, required for irreversible cell-fate specification, is preserved after RTK signaling has ended. Here we address this question using the Drosophila embryo, a model system that has been instrumental in elucidating the developmental functions of RTK signal transduction. Results: The Groucho corepressor is phosphorylated and downregulated in response to RTK signaling. Here we show that RTK pathways use Groucho phosphorylation as a general mechanism for inducing expression of pathway target genes encoding cell-fate determinants as well as feedback antagonists, indicating that relief of Groucho-dependent repression is an integral element of RTK signaling networks. We further demonstrate that after mitogen-activated protein kinase (MAPK) has been deactivated, sustained phosphorylation of Groucho is essential for persistent RTK-induced target gene expression and cell-fate determination in several developmental contexts. Conclusions: Phosphorylation of Groucho by MAPK plays a dual role in the regulation of RTK responses: (1) it mediates rapid feedback inhibition, and (2) it provides a stable memory mechanism of past MAPK activity. We propose that, in this manner, phosphorylation of Groucho enables transiently active RTK pathways to fix the spatiotemporal expression profiles of downstream targets over time.

Original languageAmerican English
Pages (from-to)1102-1110
Number of pages9
JournalCurrent Biology
Volume21
Issue number13
DOIs
StatePublished - 12 Jul 2011

Bibliographical note

Funding Information:
We thank Albert Courey, Rutie Finkelstein, Dennis Kuo, Yaron Suissa, Oren Ziv, and members of our laboratory for continued help. We are grateful to David Ish-Horowicz and Benny Shilo for their comments on the manuscript; to Benny Shilo for continuous encouragement; and to Rich Binari, Shari Carmon, Bill Chia, Christos Delidakis, Chris Doe, Greg Fish, Barbara Jennings, Yoosik Kim, Mark Krasnow, Maria Leptin, Norbert Perrimon, Benny Shilo, Stas Shvartsman, Angela Stathopoulos, Lisa Vogelsang, Talila Volk, Nir Yakoby, the Developmental Studies Hybridoma Bank, and the Bloomington Stock Centre for antibodies, fly stocks, and other reagents. This research was supported by grants from the Israel Science Foundation (Center of Excellence; 180/09) and the Król Charitable Foundation to Z.P.; G.J. was supported by the Institució Catalana de Recerca i Estudis Avançats (ICREA), the Ministerio de Ciencia e Innovación (BFU2008-01875), and the Generalitat de Catalunya (2009SGR-1075); and A.O. was supported by the Israel Science Foundation. A.H. was the recipient of a PhD fellowship from the Rector of The Hebrew University of Jerusalem.

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