Keren, a new ligand of the Drosophila epidermal growth factor receptor, undergoes two modes of cleavage

Reich, Aderet

doi:10.1093/emboj/cdf439

Cited by 69 publications

(51 citation statements)

References 40 publications

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“…Our studies clearly demonstrate that the SOS/Ras/ERK pathway is upregulated in GMR-dRet MEN2 flies: for example, eye tissue from GMRdRet MEN2B flies showed increased levels of activated diphospo-ERK. In fact, GMR-dRet MEN2 phenotypes are very similar to phenotypes conferred by retinal-specific hyperactivation of the Ras pathway Halfar et al 2001;Reich and Shilo 2002). This is consistent with numerous studies demonstrating that activation of normal and oncogenic Ret leads to recruitment of the Shc, SNT/FRS2, and Grb2 adaptor proteins to mediate Ras activation and induction of ERK signaling (van Weering et al 1995;Ohiwa et al 1997;Chiariello et al 1998;Califano et al 2000;Hayashi et al 2000;Kurokawa et al 2001;Melillo et al 2001).…”

Section: Genesupporting

confidence: 74%

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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: Genesupporting

confidence: 74%

“…, an activated version of Ras85D, and Keren, a dEGFR ligand that activates the dEGFR pathway (Bishop and Corces 1988;Karim et al 1996;Halfar et al 2001;Reich and Shilo 2002).…”

Section: V12mentioning

confidence: 99%

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

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et al. 2005

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“…As Keren and gurken mutants are viable and do not show behavioral deficits (Brown et al, 2007;Reich and Shilo, 2002;Schüpbach, 1987), we then focused our analysis on vein mutants. vein encodes the fly homolog of neuregulin 1, which regulates the ensheathment of peripheral axons in mammals (Michailov et al, 2004).…”

Section: The Neuregulin Homolog Vein Cell-autonomously Controls Wrappmentioning

confidence: 99%

Axonal wrapping in theDrosophilaPNS is controlled by glia-derived neuregulin homolog Vein

et al. 2015

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Efficient neuronal conductance requires that axons are insulated by glial cells. For this, glial membranes need to wrap around axons. Invertebrates show a relatively simple extension of glial membranes around the axons, resembling Remak fibers formed by Schwann cells in the mammalian peripheral nervous system. To unravel the molecular pathways underlying differentiation of glial cells that provide axonal wrapping, we are using the genetically amenable Drosophila model. At the end of larval life, the wrapping glia differentiates into very large cells, spanning more than 1 mm of axonal length. The extension around axonal membranes is not influenced by the caliber of the axon or its modality. Using cell typespecific gene knockdown we show that the extension of glial membranes around the axons is regulated by an autocrine activation of the EGF receptor through the neuregulin homolog Vein. This resembles the molecular mechanism employed during cell-autonomous reactivation of glial differentiation after injury in mammals. We further demonstrate that Vein, produced by the wrapping glia, also regulates the formation of septate junctions in the abutting subperineurial glia. Moreover, the wrapping glia indirectly controls the proliferation of the perineurial glia. Thus, the wrapping glia appears center stage to orchestrate the development of the different glial cell layers in a peripheral nerve.

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“…Three Drosophila Egfr ligands are activated by Rhomboid proteases: Gurken, which is only present in oocytes, Spitz and Keren (Ghiglione et al, 2002;Reich and Shilo, 2002;Urban et al, 2002), the latter expressed in embryos below the detection level of in situ hybridisation or antibody staining (Reich and Shilo, 2002;Urban et al, 2002). Thus, the ligand activated by Rho3 to guide GB1 migration is very likely Spitz, as it is expressed and is functional at the midline (Golembo et al, 1996) (data not shown), but we cannot formally exclude a contribution by Keren.…”

Section: Discussionmentioning

confidence: 99%

Rhomboid 3 orchestrates Slit-independent repulsion of tracheal branches at the CNS midline

et al. 2004

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Egfr or Ras in the leading cell of the ganglionic branch can induce premature turns away from the midline. This suggests that the level of Egfr intracellular signalling, rather than the asymmetric activation of the receptor on the cell surface, is an important determinant in ganglionic branch repulsion. We propose that Egfr activation provides a necessary switch for the interpretation of a yet unknown repellent function of the midline.

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Keren, a new ligand of the Drosophila epidermal growth factor receptor, undergoes two modes of cleavage

Cited by 69 publications

References 40 publications

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

A Drosophila Model of Multiple Endocrine Neoplasia Type 2

Axonal wrapping in theDrosophilaPNS is controlled by glia-derived neuregulin homolog Vein

Rhomboid 3 orchestrates Slit-independent repulsion of tracheal branches at the CNS midline

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