Journal
BIOCHEMICAL JOURNAL
Volume 427, Issue -, Pages 237-245Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20091011
Keywords
Filamin; c-Jun N-terminal kinase (JNK); mitogen-activated protein kinase kinase 4 (MKK4); mitogen-activated protein kinase kinase 7 (MKK7); stress-activated protein kinase (SAPK); stress-activated protein kinase/extracellular-signal-regulated kinase kinase 1 (SEK1)
Categories
Funding
- Ministry of Education, Culture, Sport, Science and Technology of Japan
- Ministry of Health, Labour and Welfare of Japan [17081005, 20390022]
- Grants-in-Aid for Scientific Research [20390022, 17081005] Funding Source: KAKEN
Ask authors/readers for more resources
SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase) belongs to the MAPK (mitogen-activated protein kinase) family and is important in many biological contexts. JNK activation is regulated by phosphorylation of specific tyrosine and threonine residues sequentially catalysed by MKK4 and MKK7, which are both dual-specificity MAPKKs (MAPK kinases). Previously, we reported that tyrosine-phosphorylation of JNK by MKK4 precedes threonine-phosphorylation by MKK7, and that both are required for synergistic JNK activation. In the present study, we identify the actin-binding protein-280 (Filamin A) as a presumed 'binder' protein that can bind to MKK7, as well as to MKK4, connecting them in close proximity. We show that Filamin family members A, B and C interact with MKK4 and MKK7, but not with JNK. Filamin A binds to an N-terminal region (residues 31-60) present in the MKK7 gamma and MKK7 beta splice isoforms, but cannot bind to MKK7 alpha which lacks these amino acids. This same N-terminal region is crucial for the intracellular co-localization of MKK7 gamma with actin stress fibres and Filamin A. Experiments using Filamin-A-deletion mutants revealed that the MKK7-binding region of Filamin A differs from its MKK4-binding region, and that MKK7 gamma (but not MKK7 alpha) can form a complex with Filamin A and MKK4. Finally, we used Filamin-A-deficient cells to show that Filamin A enhances MKK7 activation and is important for synergistic stress-induced JNK activation in vivo. Thus Filamin A is a novel member of the group of scaffold proteins whose function is to link two MAPKKs together and promote JNK activation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available