Rap1 GTPase Regulation of Adherens Junction Positioning and Cell Adhesion

Knox, Andrea L.; Brown, Nicholas H.

doi:10.1126/science.1067549

Cited by 229 publications

(222 citation statements)

References 27 publications

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“…in epithelial wing cells requires active Rap1 (44). Downstream of activated Rap1 is Canoe, the D. melanogaster ortholog of the multidomain junctional protein AF-6/afadin in vertebrates, which is required during embryonic dorsal closure, a process that relies on the movement of cohesive epithelial sheets (45).…”

Section: Discussionmentioning

confidence: 99%

Activation of Rac1 by Paxillin-Crk-DOCK180 Signaling Complex Is Antagonized by Rap1 in Migrating NBT-II Cells

Vallés

Beuvin

Boyer

2004

Journal of Biological Chemistry

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Induction of epithelial cell motility is a fundamental morphogenetic event that is recapitulated during carcinoma metastasis. Random motility of NBT-II carcinoma cells on collagen critically depends on paxillin phosphorylation at Tyr-31 and Tyr-118, the binding sites for the adapter protein CrkII. Two constitutive partners of CrkII are the exchange factors DOCK180 and C3G. CrkII bound to DOCK180 formed a signaling complex with phosphorylated paxillin that was necessary for cell migration as inferred from the inhibition caused by a DOCK180-interfering mutant. DOCK180, which acts predominantly on the Rho family GTPase Rac1, restored cell locomotion in cells expressing Phe-31/118 paxillin mutants deficient in Rac1 GTP-loading, suggesting that formation of paxillin-Crk-DOCK180 signaling complex controls collagen-dependent migration mainly through Rac1 activation. In migrating cells, CrkII constitutive association with C3G was not sufficient to stimulate its GDP/GTP exchange activity toward the Ras family GTPase Rap1. However, when constitutively active RapV12 was overexpressed, it negatively regulated cell motility. Activation of the C3G/Rap1 signaling pathway resulted in down-regulation of the paxillin-Crk-DOCK180 complex and reduction of Rac1-GTP, suggesting that Rap1 activation could suppress the Rac1 signaling pathway in epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Activation of Rac1 by Paxillin-Crk-DOCK180 Signaling Complex Is Antagonized by Rap1 in Migrating NBT-II Cells

Vallés

Beuvin

Boyer

2004

Journal of Biological Chemistry

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“…Cells lacking the AJ component Armadillo/␤-catenin do not survive in discs (Peifer et al 1991), whereas cells mutant for E-cadherin show mild polarity defects with no apparent effects on proliferation (Le Borgne et al 2002). Rap1 mutations disrupt AJs in imaginal discs, inducing ectopic cell dispersal, but do not show proliferation defects (Knox and Brown 2002). Simi- larly, imaginal disc cells lacking SJs do not overproliferate (Ward et al 1998;D.…”

Section: Polarity and Proliferation Control: Modelsmentioning

confidence: 99%

Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors

Bilder¹

2004

Genes Dev.

517

510

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Mammalian epithelial tumors lose polarity as they progress toward malignancy, but whether polarity loss might causally contribute to cancer has remained unclear. In Drosophila, mutations in the "neoplastic tumor suppressor genes" (nTSGs) scribble, discs-large, and lethal giant larvae disrupt polarity of epithelia and neuroblasts, and simultaneously induce extensive overproliferation of these cells, which exhibit malignant-like characteristics. Herein I review what is known about the role of the fly nTSGs in controlling cell polarity and cell proliferation. Incorporating data from mammalian studies, I consider how polarity and proliferation can be coupled, and how disruption of polarity could promote cancer.

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“…Rap is a Ras GTPase that has been shown to regulate actin dynamics, cell adhesion, junction formation (but not maintenance) and cell polarity (Knox and Brown, 2002;Hogan et al, 2004;Schwamborn and Puschel, 2004;Bos, 2005). For instance, Rap1 was shown to regulate E-cadherin-based cell adhesion, and inhibition of Rap1 in MDCK cells resulted in the loss of E-cadherin from the cell surface and disassembly of cell junctions (Hogan et al, 2004;Price et al, 2004).…”

Section: Cytokines and Growth Factorsmentioning

confidence: 99%