Epidermal Growth Factor Pathway Signaling in Drosophila Embryogenesis: Tools for Understanding Cancer

Lusk, Jay B; Lam, Vanessa Yuk Man; Tolwinski, Nicholas S.

doi:10.3390/cancers9020016

Cited by 32 publications

(25 citation statements)

References 89 publications

(112 reference statements)

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“…In mouse embryo fibroblasts, RAS sustains proliferation, survival, and migration through activation of RAF kinases with no apparent role for other effectors in these processes (Drosten et al, 2010). RAS proteins in Drosophila melanogaster and Caenorhabditis elegans regulate pathways that are strikingly similar to the canonical RAS-MAPK pathway in mammalian cells (Lusk et al, 2017). Indeed, genetic analysis of RAS signaling in these organisms played an important role in piecing together the RAS pathway in mammalian cells, including roles for the regulatory proteins KSR, CBL, SHOC2, and SHP2 (Figure 2).…”

Section: Ras Effectorsmentioning

confidence: 99%

RAS Proteins and Their Regulators in Human Disease

Simanshu

Nissley

McCormick

2017

Cell

1,370

1,350

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RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS’ interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases.

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Section: Ras Effectorsmentioning

confidence: 99%

RAS Proteins and Their Regulators in Human Disease

Simanshu

Nissley

McCormick

2017

Cell

1,370

1,350

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“…The reduced proliferation observed in kdm5 140 mutant wing discs is reflected in our GO analyses, with regulators of the cell cycle being significantly enriched. These included genes such as cyclin E and cdc25 that mediate cell cycle progression (BERTOLI et al 2013) in addition to components of key growth signaling pathways such as the epidermal growth factor receptor (EGFR) (LUSK et al 2017). In addition, consistent with previous studies of kdm5 mutants, genes involved in circadian rhythm, mitochondrial function and stress response were also enriched (DITACCHIO et al 2011;LIU et al 2014;GAJAN et al 2016).…”

Section: Wing Imaginal Discs From Kdm5 Null Mutants Have Gene Expressmentioning

confidence: 99%

The histone demethylase KDM5 is essential for larval growth inDrosophila

Secombe

Drelon

Belálcazar

2018

Preprint

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Regulated gene expression is necessary for developmental and homeostatic processes. The KDM5 family of proteins are histone H3 lysine 4 demethylases that can regulate transcription through both demethylase-dependent and independent mechanisms. While loss and overexpression of KDM5 proteins are linked to intellectual disability and cancer, respectively, their normal developmental functions remain less characterized. Drosophila melanogaster provides an ideal system to investigate KDM5 function, as it encodes a single ortholog in contrast to the four paralogs found in mammalian cells. To examine the consequences of complete loss of KDM5, we generated a null allele of Drosophila kdm5, also known as little imaginal discs (lid), and show that it is essential for development. Animals lacking KDM5 die during late pupal development but show a dramatically delayed larval development that coincides with decreased proliferation and increased cell death in imaginal discs. Interestingly, this developmental delay is independent of the well-characterized Jumonji C (JmjC) domainencoded histone demethylase activity and plant homedomain (PHD) motif-mediated chromatin binding activities of KDM5, suggesting key functions for less characterized domains. Consistent with the phenotypes observed, transcriptome analyses of kdm5 null mutant wing imaginal discs revealed the dysregulation of genes involved in several cellular processes, including cell cycle progression and DNA repair. Together, our data provide the first description of complete loss of KDM5 function in a metazoan and offer an invaluable tool for defining the biological activities of KDM5 family proteins.

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“…The Ras‐MAPK pathway has been shown to play an important role in cell proliferation and survival in the eye of Drosophila (Halfar et al, ). There are seven “master control” genes involved in the development of Drosophila ’s compound eyes – Pax6 homologs Eyeless ( Ey ) and Twin of Eyeless ( Toy ), the Pax2 homolog Eye Gone ( Eyg ), the Six homologs Sine Oculis ( So ) and Optix, Dachshund ( Dac ) and Eyes Absent ( Eya ) – which are controlled by epidermal growth factor (EGF) signaling in the Ras‐MAPK pathway (Kumar & Moses, ; Lusk et al, ). Interestingly, three of these genes ey, toy , and dac , are expressed in the developing MBs and have critical functions in the structural formation of the MBs (Kurusu et al, ).…”

Section: Discussionmentioning

confidence: 99%

CNKSR1 gene defect can cause syndromic autosomal recessive intellectual disability

Kazeminasab

Taskiran

Fattahi

et al. 2018

American J of Med Genetics Pt B

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The advent of high‐throughput sequencing technologies has led to an exponential increase in the identification of novel disease‐causing genes in highly heterogeneous diseases. A novel frameshift mutation in CNKSR1 gene was detected by Next‐Generation Sequencing (NGS) in an Iranian family with syndromic autosomal recessive intellectual disability (ARID). CNKSR1 encodes a connector enhancer of kinase suppressor of Ras 1, which acts as a scaffold component for receptor tyrosine kinase in mitogen‐activated protein kinase (MAPK) cascades. CNKSR1 interacts with proteins which have already been shown to be associated with intellectual disability (ID) in the MAPK signaling pathway and promotes cell migration through RhoA‐mediated c‐Jun N‐terminal kinase (JNK) activation. Lack of CNKSR1 transcripts and protein was observed in lymphoblastoid cells derived from affected patients using qRT–PCR and western blot analysis, respectively. Furthermore, RNAi‐mediated knockdown of cnk, the CNKSR1 orthologue in Drosophila melanogaster brain, led to defects in eye and mushroom body (MB) structures. In conclusion, our findings support the possible role of CNKSR1 in brain development which can lead to cognitive impairment.

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Epidermal Growth Factor Pathway Signaling in Drosophila Embryogenesis: Tools for Understanding Cancer

Cited by 32 publications

References 89 publications

RAS Proteins and Their Regulators in Human Disease

RAS Proteins and Their Regulators in Human Disease

The histone demethylase KDM5 is essential for larval growth inDrosophila

CNKSR1 gene defect can cause syndromic autosomal recessive intellectual disability

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