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An epidermal growth factor (EGF) -dependent interaction between GIT1 and sorting nexin 6 promotes degradation of the EGF receptor

Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine, Rochester, New York, USA

² Correspondence: University of Rochester, Cardiovascular Research Institute, Box 679, 601 Elmwood Ave., Rochester, NY 14642, USA. E-mail: bradford_berk{at}urmc.rochester.edu

G-protein coupled receptor (GPCR) kinase-2 interacting protein 1 (GIT1) is a multifunctional scaffolding protein that regulates epidermal growth factor receptor (EGFR) signaling pathways. We demonstrate that GIT1 interacts with sorting nexin 6 (SNX6), a member of the SNX family that increases EGFR trafficking between endosomes and lysosomes, thereby enhancing EGFR degradation. The GIT1-SNX6 interaction is increased 3-fold after treatment with EGF for 60 min. The second coiled-coil domain (CC2; aa 424–474) of GIT1 mediates binding to SNX6. Subcellular fractionation and confocal microscopy data indicate that GIT1 and SNX6 interact in endosomes. Knockdown of GIT1 expression by small interfering RNA decreased the rate of EGF-induced EGFR degradation. Expression of exogenous GIT1 or SNX6 alone did not alter EGFR degradation; however, coexpression of GIT1 and SNX6 decreased EGFR levels both basally and in response to EGF. In contrast, expression of GIT1(CC2 deleted) and SNX6 did not reduce EGFR levels, demonstrating that the interaction between GIT1 and SNX6 was required to regulate EGFR trafficking. Phosphorylation of the EGFR substrate phospholipase C- was decreased by coexpression of GIT1 and SNX6. These data demonstrate an endosomal, EGF-regulated interaction between SNX6 and GIT1 that enhances degradation of the EGFR, and thereby alters EGFR signaling. Our findings suggest a new role for GIT1 in tyrosine kinase receptor trafficking.—Cavet, M. E., Pang, J., Yin, G., Berk, B. C. An epidermal growth factor (EGF)-dependent interaction between GIT1 and sorting nexin 6 promotes degradation of the EGF receptor.

Key Words: G-protein coupled receptor • tyrosine kinase • signal transduction • endosome • receptor trafficking