Raf acts as a MAP kinase kinase kinase and activates the MAP kinase kinases MEK1 and MEK2, which, in flip, catalyze the activation of the 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 as well as the loved ones of MAP kinase kinases MEK1 and MEK2 belong to your loved ones of MAPKKs, that are dual specificity enzymes that phosphorylate threonine and tyrosine resi dues inside the activation loop of their MAP kinase substrates. The human genome encodes 7 MAPKK enzymes that regulate the exercise of four 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.
Depending on the cellular context, MKK4 may additionally contribute to your activation of the p38 pathway. Structurally, MAPKKs are proteins of 45 50 kDa that share 37 44% amino acid identity with MEK1/MEK2 supplier Fostamatinib inside the kinase domain. MEK1 and MEK2 are themselves 86% identical from the catalytic domain. Additionally to their kinase domain, MEK1 and MEK2 con tain a powerful leucine rich nuclear export signal at their N terminal extremity, a characteristic not identified in other MAPKK family members. Contrary to MAP kinases, MAPKKs have very narrow substrate specificity. It can be assumed, from lack of evidence to the contrary, that the MAP kinases ERK1/ERK2 are the only sub strates of MEK1 and MEK2. On the other hand, the probability that MEK1/MEK2 have other non catalytic effectors can’t be excluded.
Such as, a recent research showed that MEK1 interacts with peroxisome proliferator activated receptor g to induce its nuclear export and attenuate its transcriptional action. The large sequence identity in between MEK1 and MEK2, and their important similarity with MEK5 have critical pharmacological implications. To start with, this explains why compact molecule selleck chemicals signaling inhibitors MEK1/2 inhibitors devel oped thus far are non selective with regard to MEK1 and MEK2 isoforms. While it’s frequently believed that the two MAPKK isoforms are functionally equivalent, there is proof, on the other hand, that they are regulated differentially and might 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 suggested that MEK1 and MEK2 may well contribute differentially to tumorigenesis. The physiopathological relevance of those obser vations to human cancer remains unclear.