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Vol. 20, Issue 7, 1949-1959, April 1, 2009

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EphA2 Engages Git1 to Suppress Arf6 Activity Modulating Epithelial Cell–Cell Contacts

Koichi Miura^*,, Jin-Min Nam^*,, Chie Kojima^*,, Naoki Mochizuki, and Hisataka Sabe^*,

*Department of Molecular Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan; Graduate School of Biostudies, Kyoto University, Kyoto 606-8502, Japan; and Department of Structural Analysis, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan

Submitted June 2, 2008; Revised January 23, 2009; Accepted January 27, 2009
Monitoring Editor: J. Silvio Gutkind

ADP-ribosylation factor (Arf) 6 activity is crucially involved in the regulation of E-cadherin–based cell–cell adhesions. Erythropoietin-producing hepatocellular carcinoma (Eph)-family receptors recognize ligands, namely, ephrins, anchored to the membrane of apposing cells, and they mediate cell–cell contact-dependent events. Here, we found that Arf6 activity is down-regulated in Madin-Darby canine kidney cells, which is dependent on cell density and calcium ion concentration, and we provide evidence of a novel signaling pathway by which ligand-activated EphA2 suppresses Arf6 activity. This EphA2-mediated suppression of Arf6 activity was linked to the induction of cell compaction and polarization, but it was independent of the down-regulation of extracellular signal-regulated kinase 1/2 kinase activity. We show that G protein-coupled receptor kinase-interacting protein (Git) 1 and noncatalytic region of tyrosine kinase (Nck) 1 are involved in this pathway, in which ligand-activated EphA2, via its phosphorylated Tyr594, binds to the Src homology 2 domain of Nck1, and then via its Src homology 3 domain binds to the synaptic localizing domain of Git1 to suppress Arf6 activity. We propose a positive feedback loop in which E-cadherin–based cell–cell contacts enhance EphA-ephrinA signaling, which in turn down-regulates Arf6 activity to enhance E-cadherin–based cell–cell contacts as well as the apical-basal polarization of epithelial cells.

Address correspondence to: Hisataka Sabe (sabe{at}obi.or.jp)

Abbreviations used: Arf, ADP-ribosylation factor; Eph, erythropoietin-producing hepatocellular carcinoma; GAP, GTPase-activating protein; Git, G protein-coupled receptor kinase-interacting protein; GGA, Golgi-localizing, gamma-adaptin ear domain homology, ARF-binding protein; HGF, hepatocyte growth factor; MDCK, Madin-Darby canine kidney; Nck, noncatalytic region of tyrosine kinase; SLD, synaptic localizing domain.

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