AP2-associated protein kinase 1

Definition:

Regulates clathrin-mediated endocytosis by phosphorylating the AP2M1/mu2 subunit of the adaptor protein complex 2 (AP-2) which ensures high affinity binding of AP-2 to cargo membrane proteins during the initial stages of endocytosis. Isoform 1 and isoform 2 display similar levels of kinase activity towards AP2M1. Preferentially, may phosphorylate substrates on threonine residues. Regulates phosphorylation of other AP-2 subunits as well as AP-2 localization and AP-2-mediated internalization of ligand complexes. Phosphorylates NUMB and regulates its cellular localization, promoting NUMB localization to endosomes. Binds to and stabilizes the activated form of NOTCH1, increases its localization in endosomes and regulates its transcriptional activity.; (Microbial infection) By regulating clathrin-mediated endocytosis, AAK1 plays a role in the entry of hepatitis C virus as well as for the lifecycle of other viruses such as Ebola and Dengue.

References:

[1]. Sean D Conner, et al. AAK1-mediated micro2 phosphorylation is stimulated by assembled clathrin. Traffic. 2003 Dec;4(12):885-90. [Content Brief]

[2]. Sean D Conner, et al. Differential requirements for AP-2 in clathrin-mediated endocytosis. J Cell Biol. 2003 Sep 1;162(5):773-9. [Content Brief]

[3]. Erika B Sorensen, et al. AAK1 regulates Numb function at an early step in clathrin-mediated endocytosis. Traffic. 2008 Sep;9(10):1791-800. [Content Brief]

[4]. Davin M Henderson, et al. A novel AAK1 splice variant functions at multiple steps of the endocytic pathway. Mol Biol Cell. 2007 Jul;18(7):2698-706. [Content Brief]

[5]. Neetu Gupta-Rossi, et al. The adaptor-associated kinase 1, AAK1, is a positive regulator of the Notch pathway. J Biol Chem. 2011 May 27;286(21):18720-30. [Content Brief]

[6]. Sean D Conner, et al. Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis. J Cell Biol. 2002 Mar 4;156(5):921-9. [Content Brief]

[7]. Doris Ricotta, et al. Phosphorylation of the AP2 mu subunit by AAK1 mediates high affinity binding to membrane protein sorting signals. J Cell Biol. 2002 Mar 4;156(5):791-5. [Content Brief]

[8]. Gregory Neveu, et al. AP-2-associated protein kinase 1 and cyclin G-associated kinase regulate hepatitis C virus entry and are potential drug targets. J Virol. 2015 Apr;89(8):4387-404. [Content Brief]

[9]. Sven Verdonck, et al. Synthesis and Structure-Activity Relationships of 3,5-Disubstituted-pyrrolo[2,3- b]pyridines as Inhibitors of Adaptor-Associated Kinase 1 with Antiviral Activity. J Med Chem. 2019 Jun 27;62(12):5810-5831. [Content Brief]

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