Phosphatase Subfamily Auxilin
Phosphatase Classification: Superfamily CC1: Family PTEN: Subfamily Auxilin
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Evolution
Auxillins are metazoan-specific, and lost from nematodes.
Domain Structure
Most auxillins are 1000-1500 AA long, with an N-terminal GAK kinase domain, a PTEN-like phosphatase domain in the middle, and a DnaJ domain at the very C-terminus. One of the two human homologs, DNAJC6/Auxillin-1 has lost the kinase domain
Functions
Human GAK is known as Cyclin G-Associated Kinase, and associated with Cyclin G and CDK5 [1, 2, 2, 3, 4, 4, 4, 4, 5, 5, 5, 5, 5, 5, 6, 6, 6, 7, 7, 8, 9, 10, 10, 10, 10, 10, 11, 11, 12, 12, 13, 14, 15, 16, 16, 17, 17, 17, 18, 19, 20, 21, 21, 22, 23, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 40, 41, 42, 42, 43, 44, 45, 46, 47, 48]. GAK also binds AP1 and is required for endosomal sorting [49]. GAK can also localize to the nucleus and is required in a clathrin-dependent manner for mitosis [50].
Little is known about the phosphatase or kinase activities of auxilins, though one report shows that GAK phosphorylates and activates the PP2A complex [51]. The phosphatase domains of both are predicted to be inactive (HCx5R changed to HCx5A in both), though the human GAK phosphatase domain has been reported to bind phospholipids, which are also involved in clathrin-coated vesicles [52].
References
- Kanaoka Y, Kimura SH, Okazaki I, Ikeda M, and Nojima H. GAK: a cyclin G associated kinase contains a tensin/auxilin-like domain. FEBS Lett. 1997 Jan 27;402(1):73-80. DOI:10.1016/s0014-5793(96)01484-6 |
- Scheele U, Kalthoff C, and Ungewickell E. Multiple interactions of auxilin 1 with clathrin and the AP-2 adaptor complex. J Biol Chem. 2001 Sep 28;276(39):36131-8. DOI:10.1074/jbc.M106511200 |
- Kametaka S, Moriyama K, Burgos PV, Eisenberg E, Greene LE, Mattera R, and Bonifacino JS. Canonical interaction of cyclin G associated kinase with adaptor protein 1 regulates lysosomal enzyme sorting. Mol Biol Cell. 2007 Aug;18(8):2991-3001. DOI:10.1091/mbc.e06-12-1162 |
- Shimizu H, Nagamori I, Yabuta N, and Nojima H. GAK, a regulator of clathrin-mediated membrane traffic, also controls centrosome integrity and chromosome congression. J Cell Sci. 2009 Sep 1;122(Pt 17):3145-52. DOI:10.1242/jcs.052795 |
- Naito Y, Shimizu H, Kasama T, Sato J, Tabara H, Okamoto A, Yabuta N, and Nojima H. Cyclin G-associated kinase regulates protein phosphatase 2A by phosphorylation of its B'γ subunit. Cell Cycle. 2012 Feb 1;11(3):604-16. DOI:10.4161/cc.11.3.19114 |
- Lee DW, Wu X, Eisenberg E, and Greene LE. Recruitment dynamics of GAK and auxilin to clathrin-coated pits during endocytosis. J Cell Sci. 2006 Sep 1;119(Pt 17):3502-12. DOI:10.1242/jcs.03092 |
