Spatiotemporal regulation of ERK2 by dual specificity phosphatases (J Biol Chem, 2008, 283:26612-26623)

報告日期: 2009/04/21
報告時間: 15:10/16:00
報告學生: 林世杰(英文報告)
講評老師: 蔣輯武
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/980421-1.pdf

Spatiotemporal Regulation of ERK2 by Dual Specificity Phosphatases

J Biol Chem. 2008 Sep 26; 283(39):26612-23.

 

Speaker: Shih-Chieh Lin (林世杰)

Commentator: Dr. Chi-Wu Chiang (蔣輯武) 老師

Time:2009/04/21

Place: Room 602 15:10-16:00

 

Abstract

Extracellular-signal-regulated kinase 1/2 (ERK1/2), a subfamily of mitogen-activated protein kinase (MAPK), plays a critical role in diverse cellular function, such as cell proliferation, differentiation , migration and cell survival. One of the central questions concerning this signaling is how activation of the same protein kinase, ERK1/2, elicits distinct cellular outcomes. Recent studies have shown that differences in the duration, magnitude and subcellular compartmentalization of ERK activity determine the specificity of biological outcome. The dual specificity phosphatases (DUSPs) which inactivate MAPKs by scaffolding and removing activating Thr and Tyr phosphate group influence spatiotemporal aspects of MAPKs signaling. According to substrates and subcellular localizations, DUSPs can be divided by nuclear inducible DUSP, cytosoplasmic ERK DUSP, JNK/p38 DUSP and atypical DUSP. To examine the spatial and temporal aspects of ERK2 regulation, the authors used a high content imaging-based model in which endogenous ERKs were knocked down with siRNA and an adenovirus expressing wild type or mutated ERK2-GFP was added back. By using this system, the authors want to investigate possible effects of DUSPs on ERK responses to transient or sustained ERK activator (epidermal growth factor and phorbol 12,13-dibutryrate, respectively). They found that a D319N mutation of ERK which impairs DUSP binding increased ERK activity and reduced nuclear accumulation for both stimuli. Moreover, by using small interference RNA (siRNA) to simultaneously remove specific DUSPs subgroup, the authors found that nuclear inducible DUSPs and JNK/p38 DUSPs were negative and positive regulators of ERK2 signaling, respectively. Furthermore, the authors also found that JNK/p38 DUSP-promoted ERK2 signaling didn’t require protein neosynthesis but inhibited JNK/p38 signaling pathway. These data indicate that different types of DUSPs will be activated in response to different external stimuli and then modulate ERK2 signaling.

 

References:

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2.   The duration, magnitude, and compartmentalization of ERK MAP kinase activity: mechanism for providing signaling specificity. (2005) J. Cell. Sci. 118, 2997-3002

3.   Targeting dual-specificity phosphatases: manipulating MAP kinase signaling and immune response. (2007) Nat. Rev. Drug. Discov. 6, 391-403