BACKGROUND MAPKs control a wide range of biological processes including cell growth, development, inflammation, apoptosis and differentiation. The MAPK family comprises a large group of protein kinases which are activated through distinct molecular signaling pathways. Activation of extracellular signal-regulated kinases (ERKs) predominantly occurs through mitogenic stimuli such as growth factors and hormones whereas activation of c-Jun N-terminal kinase (JNK) and p38 MAPK is mainly achieved through stress stimuli and inflammatory responses. A highly complex network of protein kinases regulates the activity of MAPKs through sequential phosphorylations at critical Ser, Thr and Tyr residues. Proteins of the MAPK kinase kinase (MAPKKK) family (Raf, MEKK, MLK, ASK1) phosphorylate MAPK kinases (MAPKK), i.e. MEK1, MEK2 (targets of Raf), MEK2, MKK3, MEK5, MKK7 (targets of MEKK), MKK3, MKK4, MKK7 (targets of MLK) and MKK3, MKK4, MKK6 (targets of ASK1). The MAPKK then activate the four major families of MAPKs, i.e. ERKs (targets of MEK1, MEK2), ERK5 (target of MEK5), JNKs (targets of MKK4 and MKK7) and p38 MAPK (target of MKK3 and MKK6).1
ERK 5 is a MAP kinase family member. ERK5 is activated by MKK5 in response to EGF stimulation via a separate Ras-dependent pathway. ERK5 can also be activated in response to osmotic and oxidative stress. MKK5 is not activated by Raf but by co-transfection with MEKK3 or MEKK2. Thus, the protein kinases MEKK2/MEKK3, MKK5 and ERK5 comprise a MAP kinase signaling module, distinct from the classical MAP kinase cascade that results in the activation of ERK5 and the phosphorylation of its downstream substrates. It was shown that overexpressed MKK5 can phosphorylate and activate ERK5 at Thr219 and Tyr221. Moreover, Activated ERK5 phosphorylated itself at a number of residues, including Thr28, Ser421, Ser433, Ser496, Ser731 and Thr733. ERK5 phosphorylated at Thr219, but not Tyr221, phosphorylated itself at a similar rate to ERK5 phosphorylated at both Thr219 and Tyr221. Activated ERK5 also phosphorylated mitogen-activated protein kinase kinase 5 (MKK5) extensively at Ser129, Ser137, Ser142 and Ser149, which are located within the region inMKK5 that is thought to interact with ERK5.2
MKK5 is overexpressed in prostate cancer and is constitutively active in breast cancer cells overexpressing ErbB2. Thus these protein kinases may be important targets for anti-cancer therapy.3
1. Seger, R. & Krebs,E.G.: FASEB J.9:726-35, 1995
2. Mody, N. et al: Biochem. J. 372:567-75, 2003
3. McCracken, S.R.C. et al: Oncogene 27:2978-88, 2007
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