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The Adaptor-associated Kinase 1, AAK1, Is a Positive Regulator of the Notch Pathway.

Abstract : The Notch pathway is involved in cell-cell signaling during development and adulthood from invertebrates to higher eukaryotes. Activation of the Notch receptor by its ligands relies upon a multi-step processing. The extracellular part of the receptor is removed by a metalloprotease of the ADAM family and the remaining fragment is cleaved within its transmembrane domain by a presenilin-dependent γ-secretase activity. γ-Secretase processing of Notch has been shown to depend upon monoubiquitination as well as clathrin-mediated endocytosis (CME). We show here that AAK1, the adaptor-associated kinase 1, directly interacts with the membrane-tethered active form of Notch released by metalloprotease cleavage. Active AAK1 acts upstream of the γ-secretase cleavage by stabilizing both the membrane-tethered activated form of Notch and its monoubiquitinated counterpart. We propose that AAK1 acts as an adaptor for Notch interaction with components of the clathrin-mediated pathway such as Eps15b. Moreover, transfected AAK1 increases the localization of activated Notch to Rab5-positive endocytic vesicles, while AAK1 depletion or overexpression of Numb, an inhibitor of the pathway, interferes with this localization. These results suggest that after ligand-induced activation of Notch, the membrane-tethered form can be directed to different endocytic pathways leading to distinct fates.
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Contributor : Neetu Gupta-Rossi Connect in order to contact the contributor
Submitted on : Friday, June 10, 2011 - 10:37:08 AM
Last modification on : Thursday, April 7, 2022 - 10:10:21 AM
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Neetu Gupta-Rossi, Sara Ortica, Vannary Meas-yedid, Sara Heuss, Julien Moretti, et al.. The Adaptor-associated Kinase 1, AAK1, Is a Positive Regulator of the Notch Pathway.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2011, 286 (21), pp.18720-30. ⟨10.1074/jbc.M110.190769⟩. ⟨pasteur-00597362⟩



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