The Interaction between the <i>Drosophila</i> Secreted Protein Argos and the Epidermal Growth Factor Receptor Inhibits Dimerization of the Receptor and Binding of Secreted Spitz to the Receptor

Jin, Ming; Sawamoto, Kazunobu; Ito, Mikiko; Okano, Hideyuki

doi:10.1128/mcb.20.6.2098-2107.2000

Cited by 52 publications

(23 citation statements)

References 71 publications

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“…Our studies suggest that Kek1 is functionally similar to another Drosophila suppressor of DER signalling called Argos. Argos is also a transcriptional target of activated DER in developing tissues (Golembo et al, 1996;Wasserman and Freeman, 1998), and it has been demonstrated that Argos binds directly to DER to inhibit the binding of the natural ligand Spitz (Jin et al, 2000). However, the sequences of the two inhibitors are very distinct.…”

Section: Mechanism Of Der/erbb Binding and Inhibitionmentioning

confidence: 99%

Mechanism of inhibition of theDrosophilaand mammalian EGF receptors by the transmembrane protein Kekkon 1

et al. 2003

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The transmembrane protein Kekkon 1 (Kek1) has previously been shown to act in a negative feedback loop to downregulate the Drosophila Epidermal Growth Factor Receptor (DER) during oogenesis. We show that this protein plays a similar role in other DER-mediated developmental processes. Structure-function analysis reveals that the extracellular Leucine-Rich Repeat (LRR) domains of Kek1 are critical for its function through direct association with DER, whereas its cytoplasmic domain is required for apical subcellular localization. In addition, the use of chimeric proteins between Kek1 extracellular and transmembrane domains fused to DER intracellular domain indicates that Kek1 forms an heterodimer with DER in vivo. To characterize more precisely the mechanism underlying the Kek1/DER interaction, we used mammalian ErbB/EGFR cell-based assays. We show that Kek1 is capable of physically interacting with each of the known members of the mammalian ErbB receptor family and that the Kek1/EGFR interaction inhibits growth factor binding, receptor autophosphorylation and Erk1/2 activation in response to EGF. Finally, in vivo experiments show that Kek1 expression potently suppresses the growth of mouse mammary tumor cells derived from aberrant ErbB receptors activation, but does not interfere with the growth of tumor cells derived from activated Ras. Our results underscore the possibility that Kek1 may be used experimentally to inhibit ErbB receptors and point to the possibility that, as yet uncharacterized, mammalian transmembrane LRR proteins might act as modulators of growth factor signalling.

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Section: Mechanism Of Der/erbb Binding and Inhibitionmentioning

confidence: 99%

Mechanism of inhibition of theDrosophilaand mammalian EGF receptors by the transmembrane protein Kekkon 1

et al. 2003

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“…The requirement of Argos as an inhibitory ligand of Egfr (Jin et al, 2000) and the identification of argos rlt suggested that Egfr signaling plays a critical role in ommatidial rotation. As Egfr is very pleiotropic with multiple requirements throughout development and eye patterning in particular (Bogdan and Klambt, 2001;Casci and Freeman, 1999;Freeman, 1997;Schweitzer and Shilo, 1997;Van Buskirk and Schupbach, 1999), it is not possible to analyze the role of Egfr in ommatidial rotation using mitotic clones of null alleles.…”

Section: Ommatidial Rotation Is Controlled By Egfr Signalingmentioning

confidence: 99%

Egfr signaling regulates ommatidial rotation and cell motility in theDrosophilaeye via MAPK/Pnt signaling and the Ras effector Canoe/AF6

2003

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Epidermal Growth Factor-receptor (Egfr) signaling is evolutionarily conserved and controls a variety of different cellular processes. In Drosophila these include proliferation, patterning, cell-fate determination, migration and survival. Here we provide evidence for a new role of Egfr signaling in controlling ommatidial rotation during planar cell polarity (PCP) establishment in the Drosophila eye. Although the signaling pathways involved in PCP establishment and photoreceptor cell-type specification are beginning to be unraveled, very little is known about the associated 90° rotation process. One of the few rotation-specific mutations known is roulette (rlt) in which ommatidia rotate to a random degree, often more than 90°. Here we show that rlt is a rotation-specific allele of the inhibitory Egfr ligand Argos and that modulation of Egfr activity shows defects in ommatidial rotation. Our data indicate that, beside the Raf/MAPK cascade, the Ras effector Canoe/AF6 acts downstream of Egfr/Ras and provides a link from Egfr to cytoskeletal elements in this developmentally regulated cell motility process. We provide further evidence for an involvement of cadherins and non-muscle myosin II as downstream components controlling rotation. In particular, the involvement of the cadherin Flamingo, a PCP gene, downstream of Egfr signaling provides the first link between PCP establishment and the Egfr pathway.

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“…The first, called Argos, contains an unconventional EGF-like domain that disrupts the spacing between cysteine residues found in the activating EGF-like ligands. Argos acts as an antagonist of fly EGF receptor activity (Jin et al, 2000;Vinos and Freeman, 2000), binding to the receptor with modest affinity and inhibiting activation by other ligands. Argos is expressed in response to EGF receptor activation, and is thought to contribute to receptor inhibition events critical for proper development (Stevens, 1998).…”

Section: Negative Modulator Proteinsmentioning

confidence: 99%

Negative regulation of ErbB family receptor tyrosine kinases

Sweeney

Carraway

2004

Br J Cancer

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Receptors of the EGF receptor or ErbB family of growth factor receptor tyrosine kinases are frequently overexpressed in a variety of solid tumours, and the aberrant activation of their tyrosine kinase activities is thought to contribute to tumour growth and progression. Much effort has been put into developing inhibitors of ErbB receptors, and both antibody and small-molecule approaches have exhibited clinical success. Recently, a number of endogenous negative regulatory proteins have been identified that suppress the signalling activity of ErbB receptors in cells. These include intracellular RING finger E3 ubiquitin ligases such as cbl and Nrdp1 that mediate ErbB receptor degradation, and may include a wide variety of secreted and transmembrane proteins that suppress receptor activation by growth factor ligands. It will be of interest to determine the extent to which tumour cells suppress these pathways to promote their progression, and whether restoration of endogenous receptor-negative regulatory pathways may be exploited for therapeutic benefit. The ErbB family of receptor tyrosine kinases, consisting of the EGF receptor, ErbB2, ErbB3 and ErbB4, directs a broad range of developmental events and contributes to the malignancy of a number of tumour types. Numerous in vivo and in vitro studies have shown that ErbB signalling plays essential roles in the development and maintenance of mammary, cardiac and neural tissues, and contributes to the development of a variety of other tissues through epithelial remodelling and differentiation. The aberrant activation of ErbB receptors in tumours can occur via mutational activation, receptor overexpression, or through tumour production of autocrine growth factor ligands.Owing to the widespread role of ErbB receptor activation in tumour growth and progression, the development of ErbB inhibitors has been a subject of intense interest. Indeed, neutralising antibodies directed towards the EGF receptor or ErbB2 are either in clinical trials or have received FDA approval for the treatment of some tumours (Arteaga, 2003). Moreover, a variety of small-molecule inhibitors are being developed to target these receptors. In this light, it is of interest to look more closely at endogenous ErbB receptor-negative regulatory pathways, the mechanisms by which tumours could overcome these checks on receptor activity, and whether these mechanisms might be employed to ultimately benefit patients.Members of the mammalian ErbB family are acted upon by EGFlike growth factor ligands, which bind to receptor extracellular domains to stimulate tyrosine kinase activity. The EGF-like domain, a 40 -60 amino-acid domain characterised by six cysteine residues forming three disulphide bonds, is a very common component of the extracellular regions of a variety of proteins encompassing a wide range of functions. Only a small subset of EGF-like proteins function as activating ligands for ErbB receptors. Despite a high degree of sequence similarity, each of the ErbB receptors appears to possess distinct bioc...

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The Interaction between the Drosophila Secreted Protein Argos and the Epidermal Growth Factor Receptor Inhibits Dimerization of the Receptor and Binding of Secreted Spitz to the Receptor

Cited by 52 publications

References 71 publications

Mechanism of inhibition of theDrosophilaand mammalian EGF receptors by the transmembrane protein Kekkon 1

Mechanism of inhibition of theDrosophilaand mammalian EGF receptors by the transmembrane protein Kekkon 1

Egfr signaling regulates ommatidial rotation and cell motility in theDrosophilaeye via MAPK/Pnt signaling and the Ras effector Canoe/AF6

Negative regulation of ErbB family receptor tyrosine kinases

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