Identification of Receptor-Tyrosine-Kinase-Signaling Target Genes Reveals Receptor-Specific Activities and Pathway Branchpoints During Drosophila Development

Leatherbarrow, John R.; Halfon, Marc S.

doi:10.1534/genetics.108.098475

Cited by 8 publications

(11 citation statements)

References 46 publications

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“…Expression of the FC markers org-1, kirre (also known as dumbfounded (duf )), and RhoGAP15B all appear normal in a pnt act background, whereas, as reported previously, expression of all three expands with pan-mesodermal expression of activated Ras (Ras act ) (Fig. 3; Leatherbarrow and Halfon, 2009, Lee et al, 2003). Doublelabeling with antibodies to Biniou, a general visceral mesoderm marker (Zaffran et al, 2001), showed that the observed expansion is throughout the visceral mesoderm (Fig.…”

Section: Resultssupporting

confidence: 76%

“…4C, D), responds to Ras act and Pnt act ectopic expression in the same manner (Fig. S1E, F and Leatherbarrow and Halfon, 2009), and shows a similar Ras act -like expansion of reporter gene expression when the remaining six ETS-type sequences are mutated (construct “mib2_FC626 ETS ; Fig. 4E, F, G).…”

Section: Resultsmentioning

confidence: 79%

“…2C and Halfon et al, 2011), and expression of a constitutively active form of Pnt (Pnt act ) has no effect on expression of either the endogenous gene or the reporter (Fig. 2D and Leatherbarrow and Halfon, 2009). Similarly, mib2 expression in the visceral mesoderm is normal in embryos mutant for the ETS-domain repressor aop (yan) (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Distinct roles and requirements forRaspathway signaling in visceral versus somatic muscle founder specification

Zhou

Popadowski

Deustchman

et al. 2018

Preprint

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running title: Ras signaling in muscle development key words: myogenesis, signal integration, founder cell, muscle progenitor, fusion competent myoblast 2 1 SUMMARY 2 A fundamentally different mechanism is shown for how Ras signaling governs cell fate 3 specification in the Drosophila somatic versus visceral mesoderms, providing insight into how 4 signaling specificity is achieved.Pleiotropic signaling pathways must somehow engender specific cellular responses. In the 7 Drosophila mesoderm, Ras pathway signaling specifies muscle founder cells from among the 8 broader population of myoblasts. For somatic muscles, this is an inductive process mediated by 9 the ETS-domain downstream Ras effectors Pointed and Aop (Yan). We demonstrate here that for 10 the circular visceral muscles, despite superficial similarities, a significantly different 11 specification mechanism is at work. Not only is visceral founder cell specification not dependent 12 on Pointed or Aop, but Ras pathway signaling in its entirety can be bypassed. Our results show 13 that de-repression, not activation, is the predominant role of Ras signaling in the visceral 14 mesoderm and that accordingly, Ras signaling is not required in the absence of repression. The 15 key repressor acts downstream of the transcription factor Lameduck and is likely a member of 16 the ETS transcription factor family. Our findings fit with a growing body of data that point to a 17 complex interplay between the Ras pathway, ETS transcription factors, and enhancer binding as 18 a critical mechanism for determining unique responses to Ras signaling. 19 20 21 22Embryonic development requires that individual cells within a field acquire new, distinct fates. 23The Drosophila larval musculature has emerged as an exemplary system for investigating this 24 process, revealing important insights into the acquisition of developmental competence, 25 progressive determination of cell fate, and the integration of multiple signals at the 26 transcriptional level. It has proven to be a particularly effective model for understanding how 27 specific outcomes can be obtained from the activation of the receptor tyrosine kinase 28

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Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 79%

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Distinct roles and requirements forRaspathway signaling in visceral versus somatic muscle founder specification

Zhou

Popadowski

Deustchman

et al. 2018

Preprint

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“…Although RTKs generally stimulate a similar complement of intracellular pathways, distinct features underlying the action of those pathways can lead to differential cellular responses (Kratchmarova et al, 2005;Leatherbarrow and Halfon, 2009;Lemmon and Schlessinger, 2010;Zand et al, 2011). In particular, quantitative changes in the strength or duration of RTK signaling can give rise to diverse cellular outputs (Marshall, 1995;Greenwood and Struhl, 1997;Lemmon and Schlessinger, 2010).…”

Section: Intrinsic Differences Between Signaling Networkmentioning

confidence: 99%

The Capicua repressor – a general sensor of RTK signaling in development and disease

Jiménez

Shvartsman

Paroush

2012

Journal of Cell Science

146

186

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SummaryReceptor tyrosine kinase (RTK) signaling pathways control multiple cellular decisions in metazoans, often by regulating the expression of downstream genes. In Drosophila melanogaster and other systems, E-twenty-six (ETS) transcription factors are considered to be the predominant nuclear effectors of RTK pathways. Here, we highlight recent progress in identifying the HMG-box protein Capicua (CIC) as a key sensor of RTK signaling in both Drosophila and mammals. Several studies have shown that CIC functions as a repressor of RTK-responsive genes, keeping them silent in the absence of signaling. Following the activation of RTK signaling, CIC repression is relieved, and this allows the expression of the targeted gene in response to local or ubiquitous activators. This regulatory switch is essential for several RTK responses in Drosophila, from the determination of cell fate to cell proliferation. Furthermore, increasing evidence supports the notion that this mechanism is conserved in mammals, where CIC has been implicated in cancer and neurodegeneration. In addition to summarizing our current knowledge on CIC, we also discuss the implications of these findings for our understanding of RTK signaling specificity in different biological processes. IntroductionReceptor tyrosine kinase (RTK) signaling pathways regulate many biological processes in all metazoans. Their activities elicit diverse cellular responses, such as proliferation, differentiation, metabolism and migration, and abnormal RTK signaling can lead to multiple diseases, most notably cancer. RTK signaling is initiated following the binding of extracellular ligands to cellsurface RTKs, which then typically oligomerize, and either autoor trans-phosphorylate tyrosine residues in their intracellular domains. This, in turn, stimulates an array of intracellular signaling cascades that primarily act through the small GTPase Ras, and a core of three serine/threonine kinases [Raf, mitogenactivated protein kinase kinase (MEK) and mitogen-activated protein kinase (MAPK, also known as ERK)], but also through the phosphatidyl-inositol-3-kinase (PI3K) and phospholipase Cc (PLCc) pathways (Lemmon and Schlessinger, 2010).Because RTK signaling pathways often lead to changes in gene expression, the nuclear factors that are directly phosphorylated by components of these pathways, for example by MAPK, have a key role in the interpretation of RTK responses. In Drosophila melanogaster, where many RTK responses have been studied in detail, the best-characterized RTK-Ras-MAPK effectors belong to the ETS transcription factor superfamily. Thus, two ETS factors, the activator Pointed-P2 and the repressor Yan, mediate multiple RTK-regulated decisions and are direct substrates of MAPK (O'Neill et al., 1994;Brunner et al., 1994;Rebay and Rubin, 1995;Gabay et al., 1996;Tootle and Rebay, 2005). Similarly, ETS proteins in other species, such as Caenorhabditis elegans LIN-1 and mammalian ELK1, are important targets of Ras-MAPK

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“…In a previous screen for genes that respond differentially to different Ras pathway components, we observed that, despite responding to RTK and Ras activation, the FC gene mib2 is not regulated by the Ras effector Pnt in the visceral mesoderm (Leatherbarrow and Halfon, 2009). Expression of both mib2 RNA and a mib2-lacZ reporter gene driven by an FC-specific enhancer (mib2-FCenhancer) is normal in pnt null mutant embryos (Fig.…”

Section: Visceral Founder Cell Specification Is Independent Of the Etmentioning

confidence: 91%

Distinct roles and requirements forRaspathway signaling in visceral versus somatic muscle founder specification

et al. 2019

View full text Add to dashboard Cite

Pleiotropic signaling pathways must somehow engender specific cellular responses. In the Drosophila mesoderm, Ras pathway signaling specifies muscle founder cells from among the broader population of myoblasts. For somatic muscles, this is an inductive process mediated by the ETS-domain downstream Ras effectors Pointed and Aop (Yan). We demonstrate here that for the circular visceral muscles, despite superficial similarities, a significantly different specification mechanism is at work. Not only is visceral founder cell specification not dependent on Pointed or Aop, but Ras pathway signaling in its entirety can be bypassed. Our results show that derepression, not activation, is the predominant role of Ras signaling in the visceral mesoderm and that, accordingly, Ras signaling is not required in the absence of repression. The key repressor acts downstream of the transcription factor Lame duck and is likely a member of the ETS transcription factor family. Our findings fit with a growing body of data that point to a complex interplay between the Ras pathway, ETS transcription factors, and enhancer binding as a crucial mechanism for determining unique responses to Ras signaling.

show abstract

Identification of Receptor-Tyrosine-Kinase-Signaling Target Genes Reveals Receptor-Specific Activities and Pathway Branchpoints During Drosophila Development

Cited by 8 publications

References 46 publications

Distinct roles and requirements forRaspathway signaling in visceral versus somatic muscle founder specification

Distinct roles and requirements forRaspathway signaling in visceral versus somatic muscle founder specification

The Capicua repressor – a general sensor of RTK signaling in development and disease

Distinct roles and requirements forRaspathway signaling in visceral versus somatic muscle founder specification

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