Src and Ras are involved in separate pathways in epithelial cell scattering

Boyer, Brigitte; Roche, Serge; Denoyelle, Monique; Thiery, Jean Paul

doi:10.1093/emboj/16.19.5904

Cited by 135 publications

(95 citation statements)

References 54 publications

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“…These are similar to the modi®cations of Src occurring upon activation of the PDGF receptor (Ralston and Bishop, 1985), which reportedly re¯ect phosphorylation of residues in the amino terminus of Src and increased Src kinase activity (Gould and Hunter, 1988;Stover et al, 1996). Interestingly, Src activity has been associated with changes in cytoskeletal organization (Thomas et al, 1995;Parsons and Parsons, 1997;Brunton et al, 1997), such as those that might occur during the migration of cells (Hall et al, 1996;Boyer et al, 1997) and the retraction of neurites (Schindelholz et al, 1997).…”

Section: Discussionmentioning

confidence: 54%

“…In ®broblasts, Src has been implicated not only in carrying out the mitogenic e ects of PDGF (Twamley-Stein et al, 1993b) by activating a pathway that leads to increased Myc transcription , but also in organizing the cytoskeleton (Thomas et al, 1995) and mediating cell locomotion (Hall et al, 1996). In epithelial cells, on the other hand, Src has been shown to mediate cell scattering and morphological changes, but not mitogenic e ects (Warren et al, 1988;Rodier et al, 1995;Boyer et al, 1997). Src also seems to be essential for neuronal di erentiation of PC12 cells following stimulation with FGF or NGF (Kremer et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

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Complex formation between EphB2 and Src requires phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region

et al. 1998

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The cellular components of the neuronal signaling pathways of Eph receptor tyrosine kinases are only beginning to be elucidated. Here we show that in vivo tyrosine phosphorylation sites of the Eph receptors EphA3, EphA4, and EphB2 in embryonic retina serve as binding sites for the Src-homology 2 (SH2) domain of Src kinase. Furthermore, tyrosine-phosphorylated EphB2 was detected in Src immunoprecipitates from transfected Cos cells, indicating that EphB2 and Src can physically associate. Interestingly, a form of Src with reduced electrophoretic mobility and increased tyrosine phosphorylation was detected in Cos cells expressing tyrosine-phosphorylated EphB2, suggesting a functional interaction between EphB2 and Src. Yeast two-hybrid analysis in conjunction with site-directed mutagenesis demonstrated that phosphorylated tyrosine 611 in the juxtamembrane region of EphB2 is crucial for the interaction with the SH2 domain of Src. In contrast, binding of the carboxy-terminal SH2 domain of phospholipase Cg was not abolished upon mutation of tyrosine 611 in EphB2. Phosphopeptide mapping of autophosphorylated full-length EphB2, and wild-type and tyrosine to phenylalanine mutants of the EphB2 cytoplasmic domain fused to LexA, showed tyrosine 611 in the sequence motif YEDP as a major site of autophosphorylation in EphB2. Our mutational analysis also indicated that tyrosines 605 and 611 are important for EphB2 kinase activity. We propose Src kinase as a downstream e ector that mediates the neuron's response to Eph receptor activation.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Complex formation between EphB2 and Src requires phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region

et al. 1998

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“…Similarly, multiple signals involved in epithelial mesenchymal transformations have been shown to activate Src (reviewed in Boyer et al, 2000;Hay, 1995) and, therefore, may also change the balance of phosphorylated tyrosine residues on ␤-catenin. In some cases these two kinases may act in the same pathway; in at least one case EGF stimulated cell scattering has been shown to be mediated by activation of src and to be independent of transcriptional activity (Boyer et al, 1997). However, going beyond correlations and in vitro model systems to actually defining a role for functional inactivation of cadherin through tyrosine phosphorylation of ␤-catenin during development remains a challenge.…”

Section: The Players the Plot And Now The Stage Epithelial Mesenchymentioning

confidence: 99%

Turn‐off, drop‐out: Functional state switching of cadherins

Lilien

Balsamo

Arregui

et al. 2002

Developmental Dynamics

149

116

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The classic cadherins are a group of calcium dependent, homophilic cell-cell adhesion molecules that drive morphogenetic rearrangements and maintain the integrity of cell groups through the formation of adherens junctions. The formation and maintenance of cadherin-mediated adhesions is a multistep process and mechanisms have evolved to regulate each step. This suggests that functional state switching plays an important role in development. Among the many challenges ahead is to determine the developmental role that functional state switching plays in tissue morphogenesis and to define the roles of each of the several regulatory interactions that participate in switching. One correlate of the loss of cadherinmediated adhesion, the "turn-off" of cadherin function, is the exit, or "drop-out" of cells from neural and epithelial layers and their conversion to a motile phenotype. We suggest that epithelial mesenchymal conversions may be initiated by signaling pathways that result in the loss of cadherin function. Tyrosine phosphorylation of ␤-catenin is one such mechanism. Enhanced phosphorylation of tyrosine residues on ␤-catenin is almost invariably associated with loss of the cadherin-actin connection concomitant with loss of adhesive function. There are several tyrosine kinases and phosphatases that have been shown to have the potential to alter the phosphorylation state of ␤-catenin and thus the function of cadherins. Our laboratory has focused on the role of the nonreceptor tyrosine phosphatase PTP1B in regulating the phosphorylation of ␤-catenin on tyrosine residues. Our data suggest that PTP1B is crucial for maintenance of N-cadherin-mediated adhesions in embryonic neural retina cells. By using an L-cell model system constitutively expressing N-cadherin, we have worked out many of the molecular interactions essential for this regulatory interaction. Extracellular cues that bias this critical regulatory interaction toward increased phosphorylation of ␤-catenin may be a critical component of many developmental events.

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“…In this regard, it is known that elevation or activation of oncogenic signal transduction proteins, including Src and Ras, may contribute to tumor spread via promotion of the mesenchymal phenotype (reviewed in Thiery, 2002). For example, in the case of the rat bladder carcinoma cell model, both oncoproteins induce a mesenchymal state but use different mechanisms (Boyer et al, 1997).…”

Section: Introductionmentioning

confidence: 99%