Recombinant human biotinylated mitogen-activated protein kinase kinase 4 (MKK4), unactive, 5 µg

Background: MKK4 is a dual specificity kinase belonging to the group of MAP kinase kinase (MKKs).  MKKs are one part of three-kinase phosphorelay system “MAPK cascade” that converts extra cellular stimuli into various cellular responses such as gene expression, mitosis, and differentiation, proliferation, and cell survival/apoptosis. MKK4 as well as MKK7 are critical upstream activators of JNK signalling required for developmental programmes and responses to various extracellular stimuli.
Upon phosphorylation at Ser and Thr residues within a Ser-X-Ala-Lys-Thr motif in their activation loops by MKKKs (e.g. ASK, MEKK, MLK, and TAK) activated MKK4 is able to in turn activate JNK by dual phosphorylation of the Thr-Pro-Tyr motif. Biochemical analyses of JNK signalling revealed, that MKK4 and MKK7 cooperate in activation process of JNK. Upon phosphorylation of the Tyr residue mediated by MKK4 full activation of JNK is achieved by Thr-phosphorylation triggered by MKK7. Whereas MKK3 and MKK6 are specific p38MAPK activators different studies showed that p38α is regulated by MKK4 too. MKK4 is involved in a variety of physiological and pathophysiological processes, especially in the nervous system, heart, immune system and the development of cancer.
Recent studies revealed, that over expression of the mkk4 gene in an ovarian cancer line is linked with a reduced proliferative activity and increased apoptosis, indicating that MKK4 acts as a tumor suppressor and may represent an important therapeutic target for the treatment of ovarian cancer.

Biotinylated protein is not phosphorylated and activated by MKKs. It is suitable as substrate for kinase activity assays and for western blot analyses. 

Theoretical MW: biotinylated MEK4 / MKK4 (Fusion Protein): 45.9 kDa
Expression system: E.coli
Purification:  affinity purification using immobilized metal affinity chromatography (IMAC) resin charged with cobalt, chemically biotinylated, gel filtration
Purity: >90% (The purified fusion protein was analyzed on Coomassie stained SDS gel.) > 90% (SEC)
Protein concentration: 0.19 mg/ml
Storage buffer: 20 mM Tris-HCl, 150 mM NaCl, 1 mM DTT, 20 % glycerol, pH 8.0                                                                 
Ordering information: shipped on dry ice

Entrez Gene ID: 6416
UniProtKB: P45985

Product specific literature:

Haeusgen W, Herdegen T, Waetzig V.(2011) „The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7.” Eur J Cell Biol.90(6-7):536-44.

Taylor JL, Szmulewitz RZ, Lotan T, Hickson J, Griend DV, Yamada SD, Macleod K, Rinker-Schaeffer CW.(2008) “New paradigms for the function of JNKK1/MKK4 in controlling growth of disseminated cancer cells.” Cancer Lett. ;272(1):12-22.

Asaoka Y, Nishina H.(2010) “Diverse physiological functions of MKK4 and MKK7 during early embryogenesis.” J Biochem. ;148(4):393-401.

Remy G, Risco AM, Iñesta-Vaquera FA, González-Terán B, Sabio G, Davis RJ, Cuenda A. (2010) “Differential activation of p38MAPK isoforms by MKK6 and MKK3.” Cell Signal. 22(4):660-7.

Yeasmin S, Nakayama K, Rahman MT, Rahman M, Ishikawa M, Katagiri A, Iida K, Nakayama N, Miyazaki K.(2011) “MKK4 acts as a potential tumor suppressor in ovarian cancer.” Tumour Biol. 32(4):661-70.

Product Citations:

Kim N, Park J, Gadhe CG, Cho SJ, Oh Y, Kim D, Song K. (2014) "A Protoberberine derivative HWY336 selectively inhibits MKK4 and MKK7 in mammalian cells: the importance of activation loop on selectivity." PLoS One. 2014 Apr 23;9(4):e91037. doi: 10.1371/journal.pone.0091037. eCollection 2014.