ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

Abstract

Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries

A molluscan extracellular signal-regulated kinase is involved in host response to immune challenges in vivo and in vitro

“…When cells are exposed to various extracellular stimuli, ERK can be activated via dual phosphorylation of the TEY motif at threonine and tyrosine residues by upstream MAPKKs. Subsequently, activated ERK proteins are translocated into the nucleus and regulate the expression of ERK pathway-target genes [14,17,18]. In the present study, subcellular location analysis revealed that the green fluorescence of ChERK was mainly distributed in the cytoplasm of HEK293T cells (Fig.…”

“…In the ERK signaling pathway, MEK is the upstream activator of ERK and Raf is the upstream activator of MEK. Upon stimulation, Raf, MEK and ERK sequential activation results in ERK translocation from the cytoplasm to the nucleus where it phosphorylates numerous transcription factors that induce the expression of ERK pathway-target genes [14,17,18]. In mammals, the family of ERK kinases is divided into two groups based on their protein structure: classic MAP kinases (ERK1 and ERK2) and large MAP kinases (ERK3, ERK5, ERK7 and ERK8).…”

Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action

“…In the present study, suppression of the pathways of p44/42 and p38 MAPKs, pAkt and p-NF-jB by bufalin could be responsible for the reduction of COX-2 expression in A549 cells. The ERK1/2 and p38 MAPK signaling pathways can be activated in response to a diverse range of extracellular stimuli including mitogens, growth factors, and cytokines (Baccarini 2005;Meloche and Pouysségur 2007;Roux and Blenis 2004) and are important targets in the diagnosis and treatment of cancer (Roberts and Der 2007). Suppression of the activated EGFR and ERK1/2 and p38 MAPKs as well as Akt signaling pathways led to inhibition of the proliferation of A549 cells (Baldys et al 2007;Nguyen et al 2004;Recchia et al 2009;Su et al 2010).…”

Anthrax protective antigen is a calcium-dependent serine protease

“…Once present in the cell cytosol, EF and LF damage the cell in various ways; LF is a zinc-dependent metalloproteinase that cleaves and inactivates the mitogen-activated protein kinase (MAPK) kinases 1–4, 6 and 7 [6]. The cleavage events result in inactivation of the MAPK pathways thereby hampering a variety of cellular responses including cell division, apoptosis, and survival [7]. EF is a calmodulin-dependent adenylyl cyclase that elevates intracellular cAMP levels by converting ATP to cAMP, the classical second messenger, thereby causing diverse adverse side-effects [8].…”