Raf acts like a MAP kinase kinase kinase and activates the MAP kinase kinases MEK1 and MEK2, which, in flip, catalyze the activation of your effector MAP kinases ERK1 and ERK2. Once activated, ERK1/ERK2 phos phorylate a panoply of nuclear and cytoplasmic sub strates concerned in diverse cellular responses, this kind of as cell proliferation, survival, differentiation, motility, and angiogenesis. MEK1/MEK2 and the household of MAP kinase kinases MEK1 and MEK2 belong to your family members of MAPKKs, which are dual specificity enzymes that phosphorylate threonine and tyrosine resi dues within the activation loop of their MAP kinase substrates. The human genome encodes 7 MAPKK enzymes that regulate the exercise of 4 distinct MAP kinase pathways. Other than MEK1/MEK2, the MAPKKs MKK4 and MKK7 phos phorylate and activate the c Jun N terminal kinase isoforms, MKK3 and MKK6 phosphorylate and activate the p38 isoforms, and MEK5 selectively acti vates ERK5.
Based on the cellular context, MKK4 might also contribute towards the activation in the p38 pathway. Structurally, MAPKKs are proteins of 45 50 kDa that share 37 44% amino acid identity with MEK1/MEK2 selleck chemicals in the kinase domain. MEK1 and MEK2 are themselves 86% identical while in the catalytic domain. Additionally to their kinase domain, MEK1 and MEK2 con tain a powerful leucine wealthy nuclear export signal at their N terminal extremity, a characteristic not located in other MAPKK family members. Contrary to MAP kinases, MAPKKs have quite narrow substrate specificity. It’s assumed, from lack of proof to your contrary, the MAP kinases ERK1/ERK2 are the only sub strates of MEK1 and MEK2. On the other hand, the likelihood that MEK1/MEK2 have other non catalytic effectors can’t be excluded.
For example, a latest review showed that MEK1 interacts with peroxisome proliferator activated receptor g to induce its nuclear export and attenuate its transcriptional action. The higher sequence identity involving MEK1 and MEK2, and their substantial similarity with MEK5 have crucial pharmacological implications. Initially, this explains why tiny molecule discover this MEK1/2 inhibitors devel oped to date are non selective with regard to MEK1 and MEK2 isoforms. Though it truly is commonly believed the two MAPKK isoforms are functionally equivalent, there exists proof, having said that, they are regulated differentially and may not be interchangeable in all cellular contexts. Intriguingly, it’s been reported that activated MEK1 but not MEK2 induces epidermal hyperplasia in transgenic mice. RNA interference and gene invali dation studies have also recommended that MEK1 and MEK2 might contribute differentially to tumorigenesis. The physiopathological relevance of those obser vations to human cancer stays unclear.