Kinase Subfamily ERK3

Kinase Classification: Group CMGC: Family MAPK: Subfamily ERK3

ERK3 (Extracellular signal Regulated Kinase 3) is a poorly-studied subfamily of MAPK. The family is eumetazoan-specific (i.e. in animals other than sponges), but is lost from both nematodes and insects. Mammals have two members, ERK3 and ERK4 (aka MAPK6 and MAPK4).

ERK3 lacks the TxY motif of most other MAPK, replacing it with SEG (in mammals). The S is known to be phosphorylated, so may act as a more traditional activation loop. Human Erk3 and Erk4 are activated by phosphorylation by PAKA kinases, and in turn can bind and activate MK5 kinase [1]. MK5 is also lost in nematodes and insects.

Domain Structure

Like ERK7, ERK3 has an N-terminal kinase domain with a long C-terminal uncharacterized region, no known upstream activating kinase, and is controlled by ubiquitination and proteasome-mediated turnover.

Functions

Mouse knockouts show a specific role for Erk3 in fetal growth, which is not shared with Erk4 [2]. Other studies link Erk3 to cell cycle via binding of CDC14 [3] and Cyclin D [4].

References

1. Aberg E, Torgersen KM, Johansen B, Keyse SM, Perander M, and Seternes OM. Docking of PRAK/MK5 to the atypical MAPKs ERK3 and ERK4 defines a novel MAPK interaction motif. J Biol Chem. 2009 Jul 17;284(29):19392-401. DOI:10.1074/jbc.M109.023283 |
2. Rousseau J, Klinger S, Rachalski A, Turgeon B, Déléris P, Vigneault E, Poirier-Héon JF, Davoli MA, Mechawar N, El Mestikawy S, Cermakian N, and Meloche S. Targeted inactivation of Mapk4 in mice reveals specific nonredundant functions of Erk3/Erk4 subfamily mitogen-activated protein kinases. Mol Cell Biol. 2010 Dec;30(24):5752-63. DOI:10.1128/MCB.01147-10 |
3. Hansen CA, Bartek J, and Jensen S. A functional link between the human cell cycle-regulatory phosphatase Cdc14A and the atypical mitogen-activated kinase Erk3. Cell Cycle. 2008 Feb 1;7(3):325-34. DOI:10.4161/cc.7.3.5354 |
4. Sun M, Wei Y, Yao L, Xie J, Chen X, Wang H, Jiang J, and Gu J. Identification of extracellular signal-regulated kinase 3 as a new interaction partner of cyclin D3. Biochem Biophys Res Commun. 2006 Feb 3;340(1):209-14. DOI:10.1016/j.bbrc.2005.12.003 |
5. Déléris P, Trost M, Topisirovic I, Tanguay PL, Borden KL, Thibault P, and Meloche S. Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase 5 signaling pathway. J Biol Chem. 2011 Feb 25;286(8):6470-8. DOI:10.1074/jbc.M110.181529 |