Requirements of genetic interactions betweenSrc42A, armadilloandshotgun, a gene encoding E-cadherin, for normal development inDrosophila

Takahashi, Mayuko; Takahashi, Fumitaka; Ui-Tei, Kumiko; Kojima, Takao; Saigo, Kaoru

doi:10.1242/dev.01850

Cited by 74 publications

(121 citation statements)

References 73 publications

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“…3F). A similar localization of SRC42A has been reported previously (Takahashi et al, 2005) and DRL is also present in AC axonal projections (Bonkowsky et al, 1999;Callahan et al, 1995). SRC64B, SRC42A and DRL are therefore expressed in AC axonal projections, supporting our observations that they functionally interact there.…”

Section: Src64b and Drl Are Both Expressed In Ac Axonssupporting

confidence: 91%

“…Quantitation of these phenotypes is presented in Table 1. These results and the similar commissural phenotypes observed in a previous study examining SFK roles during Drosophila embryonic development (Takahashi et al, 2005) suggest that the Drosophila SFKs play partially redundant roles in the formation of the embryonic commissures.…”

Section: Sfks Are Required For Embryonic Commissure Formationsupporting

confidence: 87%

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Src family kinases are required for WNT5 signaling through the Derailed/RYK receptor in theDrosophilaembryonic central nervous system

et al. 2008

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Members of the RYK/Derailed family have recently been shown to regulate axon guidance in both Drosophila and mammals by acting as Wnt receptors. Little is known about how the kinase activity-deficient RYKs transduce Wnt signals. Here, we show that the non-receptor Src family tyrosine kinases, SRC64B and SRC42A, are involved in WNT5-mediated signaling through Derailed in the Drosophila embryonic central nervous system. Analysis of animals lacking SRC64B and SRC42A reveals defects in commissure formation similar to those observed in Wnt5 and derailed mutants. Reductions in SRC64B expression levels suppress a Wnt5/derailed-dependent dominant gain-of-function phenotype, and increased levels of either SRC64B or SRC42A enhance Wnt5/derailed-mediated axon commissure switching. Derailed and SRC64B form a complex, which contains catalytically active SRC64B, the formation or stability of which requires SRC64B kinase activity. Furthermore, Derailed is phosphorylated in a SRC64B-dependent manner and coexpression of Derailed and SRC64B results in the activation of SRC64B. The mammalian orthologs of Derailed and SRC64B also form complexes, suggesting that Src roles in RYK signaling are conserved. Finally, we show that coexpression of WNT5 and Derailed has no apparent effect upon TCF/LEF-dependent transcription, suggesting that the WNT5/Derailed signaling pathway is unlikely to directly regulate canonical Wnt pathway targets. Together, these findings indicate that the Src family kinases play novel roles in WNT5/Derailed-mediated signaling.

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Section: Src64b and Drl Are Both Expressed In Ac Axonssupporting

confidence: 91%

Section: Sfks Are Required For Embryonic Commissure Formationsupporting

confidence: 87%

Src family kinases are required for WNT5 signaling through the Derailed/RYK receptor in theDrosophilaembryonic central nervous system

et al. 2008

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“…These axons depend on repulsive SlitRobo signaling for pathfinding (Seeger et al, 1993;Kidd et al, 1998), but often cross in embryos in which adhesion has been reduced as well, as seen in integrin loss-of-function mutants (Loureiro and Peifer, 1998;Speicher et al, 1998;Stevens and Jacobs, 2002). Accompanying these CNS malformations are profound patterning defects including partial head involution, defective dorsal closure, and a failure of germ-band retraction, as reported previously (Lu and Li, 1999;Takahashi et al, 2005). Because we observe these patterning defects, and because midline and lateral glia are frequently mispositioned in these mutants (Wouda et al, 2008) (data not shown), it is difficult to conclusively interpret the CNS phenotype in these embryos.…”

Section: Resultssupporting

confidence: 62%

Src Inhibits Midline Axon Crossing Independent of Frazzled/Deleted in Colorectal Carcinoma (DCC) Receptor Tyrosine Phosphorylation

O’Donnell

Bashaw

2013

J. Neurosci.

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The phylogenetically conserved Netrin family of chemoattractants signal outgrowth and attractive turning of commissural axons through the Deleted in Colorectal Carcinoma (DCC) family of receptors. Src family kinases are thought to be major signaling effectors of Netrin/ DCC. In vertebrates, Src and the closely related Fyn kinases phosphorylate DCC and form a receptor-bound signaling complex leading to activation of downstream effectors. Here we show that, in the Drosophila embryonic CNS, Src kinases are dispensable for midline attraction of commissural axons. Consistent with this observation, tyrosine phosphorylation of the Netrin receptor DCC or its Drosophila ortholog, Frazzled, is not necessary for attraction to Netrin. Moreover, we uncover an unexpected function of Src kinases: inhibition of midline axon crossing through a novel mechanism. We propose that distinct signaling outputs must exist for midline axon crossing independent of Src kinases in commissural neurons.

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“…This might be inferred from earlier studies, but they are not directly comparable. Reports documenting a positive impact of SFK signaling on cadherin function generally used loss-of-function approaches (Takahashi et al, 1996(Takahashi et al, , 2005Calautti et al, 1998), whereas negative effects of SFK signaling have generally been identified when constitutively active SFK mutants were overexpressed in cells, as a gain-offunction approach (Warren and Nelson, 1987;Volberg et al, 1991;Matsuyoshi et al, 1992;Behrens et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…However, this fails to occur in fyn-deficient cells, which also display defects in adherens junction assembly (Calautti et al, 1998). Similarly, junctional assembly and dorsal closure were perturbed in Src42A-deficient flies (Takahashi et al, 1996(Takahashi et al, , 2005. The discrepancy between these different sets of studies has yet to be resolved.…”

Section: Introductionmentioning

confidence: 99%

E-Cadherin Adhesion Activates c-Src Signaling at Cell–Cell Contacts

McLachlan

Kraemer²,

Helwani³

et al. 2007

MBoC

138

141

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Cadherin-based cell-cell contacts are prominent sites for phosphotyrosine signaling, being enriched in tyrosine-phosphorylated proteins and tyrosine kinases and phosphatases. The functional interplay between cadherin adhesion and tyrosine kinase signaling, however, is complex and incompletely understood. In this report we tested the hypothesis that cadherin adhesion activates c-Src signaling and sought to assess its impact on cadherin function. We identified c-Src as part of a cadherin-activated cell signaling pathway that is stimulated by ligation of the adhesion receptor. However, c-Src has a biphasic impact on cadherin function, exerting a positive supportive role at lower signal strengths, but inhibiting function at high signal strengths. Inhibiting c-Src under circumstances when it is activated by cadherin adhesion decreased several measures of cadherin function. This suggests that the cadherin-activated c-Src signaling pathway serves positively to support cadherin function. Finally, our data implicate PI3-kinase signaling as a target for cadherin-activated c-Src signaling that contributes to its positive impact on cadherin function. We conclude that E-cadherin signaling is an important activator of c-Src at cell-cell contacts, providing a key input into a signaling pathway where quantitative changes in signal strength may result in qualitative differences in functional outcome. INTRODUCTIONClassical cadherin cell adhesion molecules are fundamental determinants of tissue organization whose biological function is intimately linked to cell signaling. Diverse signaling molecules are found at cell-cell contacts and many are activated in a cadherin-dependent manner when cells adhere to one another . Among the relevant signals, it has long been recognized that cadherin adhesions are major sites for protein tyrosine phosphorylation. Many tyrosine-phosphorylated proteins are found at adherens junctions, which are, indeed, conspicuous sites for phosphotyrosine staining in cells (Takata and Singer, 1988;Tsukita et al., 1991;Calautti et al., 1998). Moreover, a wide range of tyrosine kinases are found at cell-cell contacts, including both receptor tyrosine kinases and cytoplasmic kinases (Tsukita et al., 1991;Thomas and Brugge, 1997;Calautti et al., 1998). However, the precise relationship between cadherin adhesion and tyrosine kinase signaling remains poorly understood. This is exemplified by c-Src and other Src-family kinases (SFKs). Members of this family of cytoplasmic tyrosine kinases are often found at cadherin-based cell-cell contacts (Tsukita et al., 1991;Calautti et al., 1998). A variety of studies further reported that expression of v-Src or constitutively active (CA) Src perturbs the integrity of cell-cell interactions in epithelia (Warren and Nelson, 1987;Volberg et al., 1991). This was accompanied by tyrosine phosphorylation of components of the cadherin/ catenin complex, notably ␤-catenin (Matsuyoshi et al., 1992;Behrens et al., 1993). Together these have led to the common notion that SFK signaling negati...

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Requirements of genetic interactions betweenSrc42A, armadilloandshotgun, a gene encoding E-cadherin, for normal development inDrosophila

Abstract: Screening of dominant enhancers for sev-Src42A[KR]Enhancers were searched for using P[sev-Src42A[KR]] (Takahashi et al., 1996) inserted into CyO or TM3 balancers. E(7A-1), which is incapable of complementing shg R64a

Cited by 74 publications

References 73 publications

Src family kinases are required for WNT5 signaling through the Derailed/RYK receptor in theDrosophilaembryonic central nervous system

Src family kinases are required for WNT5 signaling through the Derailed/RYK receptor in theDrosophilaembryonic central nervous system

Src Inhibits Midline Axon Crossing Independent of Frazzled/Deleted in Colorectal Carcinoma (DCC) Receptor Tyrosine Phosphorylation

E-Cadherin Adhesion Activates c-Src Signaling at Cell–Cell Contacts

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