An EGFR/Ebi/Sno Pathway Promotes Delta Expression by Inactivating Su(H)/SMRTER Repression during Inductive Notch Signaling

Tsuda, Leo; Nagaraj, Raghavendra; Zipursky, S. Lawrence; Banerjee, Utpal

doi:10.1016/s0092-8674(02)00875-9

Cited by 157 publications

(207 citation statements)

References 66 publications

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“…The suppressing deficiencies Df(2L)net-PMF (21A1;21B8) and Df(2L)al (21B8;21D1) contain the genes kismet and ebi, respectively (Table 2). Both kismet and ebi are involved in chromatin remodeling and are positive regulators of dEGFR and Ras signaling in the retina (Therrien et al 2000;Tsuda et al 2002). Mutations in either locus suppressed GMR-dRet phenotypes.…”

Section: Men2amentioning

confidence: 99%

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

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et al. 2005

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Dominant mutations in the Ret receptor tyrosine kinase lead to the familial cancer syndrome multiple endocrine neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that Ret MEN2 mutations significantly alter Ret-signaling properties, but the precise mechanisms by which Ret MEN2 promotes tumorigenesis remain poorly understood. To determine the signal transduction pathways required for Ret MEN2 activity, we analyzed analogous mutations in the Drosophila Ret ortholog dRet. Overexpressed dRet MEN2 isoforms targeted to the developing retina led to aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analysis indicated that dRet MEN2 acts through the Ras-ERK, Src, and Jun kinase pathways. A genetic screen for mutations that dominantly suppress or enhance dRet MEN2 phenotypes identified new genes that are required for the phenotypic outcomes of dRet MEN2 activity. Finally, we identified human orthologs for many of these genes and examined their status in human tumors. Two of these loci showed loss of heterozygosity (LOH) within both sporadic and MEN2-associated pheochromocytomas, suggesting that they may contribute to Ret-dependent oncogenesis. D URING development, receptor tyrosine kinases (RTKs) integrate extracellular signals to influence cellular processes such as growth and differentiation. Signaling through RTKs requires ligand-induced oligomerization to direct tyrosine autophosphorylation; autophosphorylation both stimulates catalytic activity and creates phospho-tyrosine docking sites for cytoplasmic proteins that activate intracellular signaling pathways. To date, mutations in more than half of all RTKs have been implicated in human cancer (reviewed in Blume-Jensen and Hunter 2001). These mutations commonly function by relieving RTK regulatory constraints, leading to inappropriate kinase activity and hyperactivation of downstream pathways. These events promote oncogenic transformation by driving aberrant cellular growth, proliferation, and survival. Still, tumorigenesis requires mutations in multiple loci: along with dominant mutations in oncogenes such as RTKs, tumorigenesis also requires loss-of-function mutations in tumor suppressors. The relationship between oncogenic tyrosine kinases and tumor suppressors, and the extent to which mutations in each cooperate to direct oncogenic growth, is not well understood.The Ret RTK plays an essential role in both development and oncogenesis. During embryogenesis, Ret is required for development of the sympathetic and enteric nervous systems, the neural crest, and the excretory system (Schuchardt et al. 1994;Durbec et al. 1996;Enomoto et al. 2001). The extracellular portion of Ret contains cysteine repeats and a cadherinlike domain. The intracellular portion of Ret contains a tyrosine kinase catalytic domain and multiple tyrosine autophosphorylation sites. Four activating ligands have been identified: GDNF, Neurturin, Persephin, and Artemin all activate Ret through the GPI-linked co-

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Section: Men2amentioning

confidence: 99%

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

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et al. 2005

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“…Given that EGFR activation appears to contribute more than just a permissive survival signal in the developing eye, the ability of undifferentiated cells to respond differently to the same signal has led to the suggestion of a combinatorial code that integrates EGFR-mediated inputs with other factors to specify all the necessary cell types (Freeman, 1997;Kumar and Moses, 1997;Hayashi and Saigo, 2001;Tsuda et al, 2002). Because the larval eye imaginal disc contains a temporal gradient of ommatidial maturity, reflecting the progression of the MF, perhaps the particular factors that make up the code are expressed at different positions relative to the MF.…”

Section: Egfr Signaling Is Required For All Eye Cell Fates Except R8:mentioning

confidence: 99%

“…Somehow cells must already know the appropriate response when stimulated by a particular combination of such semipermissive instructions. To explain this, researchers have proposed that the exact response of undifferentiated cells to a particular combination of RTK and Notch signals changes over time (Freeman, 1997;Kumar and Moses, 1997;Hayashi and Saigo, 2001;Tsuda et al, 2002). If this is true, then there must be distinct "competence zones" posterior to the MF, with changes in cellular competence governed by the expression of different transcription factors.…”

Section: Combinatorial Code Specifying Photoreceptor Fatementioning

confidence: 99%

“…Thus, Ttk88 stability is the critical readout of varying degrees of Ras pathway activation that distinguishes cone cell fate from R7 fate. The Notch pathway is also required for cone cell specification (Cagan and Ready, 1989;Parks et al, 1995;Tsuda et al, 2002). Part of this function is related to the transcription of differentiation factors like D-Pax2 (Flores et al, 2000).…”

Section: Cone Cellsmentioning

confidence: 99%

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Signal integration during development: Insights from the Drosophila eye

Voas

Rebay

2003

Developmental Dynamics

162

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The Drosophila eye is a highly ordered epithelial tissue composed of ϳ750 subunits called ommatidia arranged in a reiterated hexagonal pattern. At higher resolution, observation of the constituent photoreceptors, cone cells, and pigment cells of the eye reveals a highly ordered mosaic of amazing regularity. This relatively simple organization belies the repeated requirement for spatially and temporally coordinated inputs from the Hedgehog (Hh), Wingless (Wg), Decapentaplegic (Dpp), JAK-STAT, Notch, and receptor tyrosine kinase (RTK) signaling pathways. This review will discuss how signaling inputs from the Notch and RTK pathways, superimposed on the developmental history of a cell, facilitate context-specific and appropriate cell fate specification decisions in the developing fly eye. Lessons learned from investigating the combinatorial signal integration strategies underlying Drosophila eye development will likely reveal cell-cell communication paradigms relevant to many aspects of invertebrate and mammalian development. Developmental Dynamics 229:162-175, 2004.

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“…Inducers of cell stress, including arsenic trioxide and anisomycin, can also activate MEKK1 and are potent inhibitors of SMRT function; this MEKK1-dependent mechanism may contribute to the prodifferentiation effects of arsenic trioxide as used in the treatment of acute promyelocytic leukemia (44). The Drosophila EGF receptor has also been shown to regulate the function of the Drosophila SMRTER protein, although whether SMRTER is a true ortholog of mammalian SMRT remains unclear (66). Reciprocally, it has been reported that N-CoR, but not SMRT, can be inhibited in certain contexts in response to TAB2 and Akt pathways operating downstream of cytokine and ciliary neurotrophic factors (51,61).…”

Section: Mekk1 Is One Of Several Signals Operating Downstream Of Growmentioning

confidence: 99%

SMRT and N-CoR Corepressors Are Regulated by Distinct Kinase Signaling Pathways

Jonas¹,

Privalsky

2004

Journal of Biological Chemistry

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N-CoR and SMRT are corepressor paralogs that partner with and mediate transcriptional repression by a wide variety of metazoan transcription factors, including nuclear hormone receptors. Although encoded by distinct genetic loci, N-CoR and SMRT share substantial sequence interrelatedness, form analogous assemblies with histone deacetylases and auxiliary factors, can interact with overlapping sets of transcription factor partners, and exert overlapping functions in cells. SMRT is subject to negative regulation by MAPK signaling pathways operating downstream of growth factor and stress signaling pathways. We report here that whereas activation of MEKK1 leads to phosphorylation of SMRT, its dissociation from its transcription factor partners in vivo and in vitro, and its redistribution from the cell nucleus to a cytoplasmic compartment, N-CoR is refractory to all these forms of regulation. In contrast to this MAPK cascade, other signal transduction pathways operating downstream of growth factor/cytokine receptors appear able to affect both corepressor paralogs. Our results indicate that SMRT and N-CoR are embedded in distinct regulatory networks and that the two corepressors interpret growth factor, cytokine, differentiation, and prosurvival signals differently.

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An EGFR/Ebi/Sno Pathway Promotes Delta Expression by Inactivating Su(H)/SMRTER Repression during Inductive Notch Signaling

Cited by 157 publications

References 66 publications

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

Signal integration during development: Insights from the Drosophila eye

SMRT and N-CoR Corepressors Are Regulated by Distinct Kinase Signaling Pathways

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