Principles of Cell Signaling and Biological Consequences
Student #1 Response to Student #6
20 May 2005
student number 1
A global corepressor, Groucho (Gro) and its mammalian homologues mediates many repression activities observed in other transcription repressors. Gro and Gro-dependent repressors are downstream effectors of several pathways (Paroush,Z. et al Cell, 1994; Giagtzoglou, N et al Development, 2003; Chen, G. et al Gene, 2000). Thus, it is an interesting molecule to examine and most probable in its function as a signal integration node between these different signal cascades. This paper elucidated the cross-talk between EGFR and Notch signaling pathways, observed previously (de Celis et al, Development, 1997; Zur Lag et al, Development, 1999), is mechanistically mediated via Gro. The authors convincingly demonstrated that RTK (ie. EGFR, MAPK) mediated Gro phosphorylation resulted in decreased Gro repressive activity. Using constitutively active EGFR and kinase assay with synthetic phosphopeptide of the presumed phosphorylation site, the authors showed that Gro is indeed phosphorylated downstream of EGFR and specifically by Erk2 of MAPK pathway. Perhaps, the most convincing and biologically relevant data came from studies of Gro phosphorylation in Drosophila model system. Authors found that phospho-mimic Gro leads to additional wing vein development; while, the phosphor-deficient-mimic Gro leads to decreased wing vein development. Analogous observation is made when authors examined notal bristles formations. These data, both in vitro and in vivo, are very strong evidence that RTK pathway modulate Gro function via phosphorylation to antagonize Notch signaling. Thus, Groucho is the cross-talk node between these two pathways.
I agree with other students that this paper demonstrated convincingly, both via biochemical and animal studies, that Gro is the crosstalk molecule between the EGFR and Notch signaling. Although, I would like to see what happens if one would knockout Groucho via tissue specific siRNA constructs. I wonder if Groucho is the only molecule that links EGFR and Notch signaling. Additionally, being a global corepressor, Groucho's phosphorylation status may have many unforeseen functions. Thus, I wonder if Gro's phosphorylation status may have an effect on other upstream pathways that feeds into Gro.
Cell. 1994 Dec 2;79(5):805-15. Groucho is required for Drosophila neurogenesis, segmentation, and sex determination and interacts directly with hairy-related bHLH proteins. Paroush Z, Finley RL Jr, Kidd T, Wainwright SM, Ingham PW, Brent R, Ish-Horowicz D. [PubMed]
Development. 2003 Jan;130(2):259-70. Two modes of recruitment of E(spl) repressors onto target genes. Giagtzoglou N, Alifragis P, Koumbanakis KA, Delidakis C.[PubMed] [Online Journal] [Full Text in Virtual Journal]de Celis, J.F. & Bray, S. Garcia-Bellido, A. Notch signalling regulates veinlet expression and establishes boundaries between veins and interveins in the Drosophila wing. Development 124, 1919−1928 (1997). [PubMed] [Online Journal]
zur Lage, P. & Jarman, A.P. Antagonism of EGFR and notch signalling in the reiterative recruitment of Drosophila adult chordotonal sense organ precursors. Development 126, 3149−3157 (1999). [PubMed] [Online Journal]