Mitogen-activated protein kinases (MAPKs) are Ser/Thr kinases which act as intermediates within the signaling cascades of both growth/survival factors, such as EGF, and death receptors, such as the TNF receptor.  via mitogen-activated protein (MAP) kinases plays an important role in cellular responses including growth factor-induced cell proliferation, differentiation, and survival. The MAPK proteins are important upstream regulators of transcription factor activities and their signaling is critical to the transduction of a wide variety of extracellular stimuli into intracellular events. MAPKs such as extracellular receptor kinase (ERK), p38, and the c-Jun NH2-terminal kinase (JNK) mediate leukocyte responses to diverse stimuli. Among the four MAP kinase pathways (Erk, Jnk, p38 and Erk5 or BMK), the Jnk and p38 pathways are closely linked with inflammation. 

MAPKs act by phosphorylating and activating downstream effector nuclear kinases. The MAPK may be present in both cytosolic and nuclear compartment, where they phosphorylate transcription factors such as Elk-1, C/EBP?, activating transciption factor (ATF)-2, C-jun, and . 

MAPK Activation:

In response to different stimuli, including , growth factors, and cellular stress, MAP kinase pathways transmit signals through a stepwise series of kinases. In each of these pathways, an upstream MAP kinase kinase kinase (MKKK) becomes phosphorylated and in turn phosphorylates a downstream MAP kinase kinase (MKK), which in turn phosphorylates a MAP kinase. The activated MAP kinase then phosphorylates transcription factors or other protein kinases to alter cellular function. 

Each of the three major MAP kinase pathways is named for the terminal MAP kinase, i.e., ERK (extracellular signal-regulated kinase), p38 and JNK/SAPK (c-Jun NH2-terminal kinase/stress-activated protein kinase). These kinases are activated by MAP kinase kinases (MKKs) which phosphorylate threonine and tyrosine residues in the Thr-X-Tyr activation motif. Upon activation, MAP kinases can migrate to the nucleus where they phosphorylate and activate transcription factors such as . Each MAP kinase family targets a different set of transcription factors. 

Extracellular signal-regulated protein kinases (ERKs)

The ERK pathway appears mainly to respond to mitogens and growth factors that regulated cell proliferation and differentiation. ERKs are believed to be strongly activated and to play a critical role in transmitting signals initiated by growth-inducing tumor promoters, including 12-O-tetradecanoyl-phorbol-13-acetate (TPA), epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). 

Blockage of the ERK pathway through pharmacological inhibition has previously been shown to induce apoptotic cell death in endothelial cells.

Activation of ERK1/2 is associated with pro-survival signalling. 

The ERK pathway has been reported to stabilize granulocyte/macrophage colony stimulating factor mRNA. 

MEK1/2 is an upstream activator of ERK 1/2. The MAP kinase (MEK) inhibitor: PD98059

It has been reported that ERK along with  negatively regulate the phenotypic and functional maturation of MoDCs and that inhibition of ERK or PI3K by selective inhibitors (PD98059 or LY294002) significantly enhance the phenotypic and functional matural of human MoDCs. Unexpectedly, PD98059 treatment of a macrophage cell line increased rather than decreased mTLR2 mRNN, suggesting that ER activation may inhibit TLR2 mRNA expression.

LPS Activation of ERK is reportedly little affected and even enhanced by EGCG in murine peritonela exudate cells from BAL/c mice. Interestingly, EGCG reported inhibited phosphorylation of p38 MAP kinases with a concomitant downregulation of IL-12p40 production. In contrast, activation of ERK MAP kianses weas inhibited little or rather enhanced by EGCG in murine macrophages.

ERK inhbitors: PD98059 (Calbiochem), is an inhibitor of ERK phosphorylation; U0126 

C-Jun N terminal kinases (JNKs)

JUN amino-terminal kinase (JNK) is a MAP kinase known to be crucial for T-cell function. Jun is a nuclear proto-oncogene, which constitutes a part of the transcription factor . JNK regulates activator protein-1 (AP-1) transcription in response to environmental stress such as UV exposure.The JNK pathway increases transcriptional activity of AP-1 by binding to and phosphorylating c-Jun.  Increased AP-1 activity has been shown to be involved in the promotion and progression of various types of cancers and also other processes such as inflammation, invasion, metastasis and angiogenesis. 

The JNK and p38SAPK pathways are predominantly activated by stress, such as osmotic changes and heat shock, but also by inflammatory cytokines such as IL-1? and TNF-?. 

JNK activation has been strongly linked to apopoptic signalling through phosphorylation of c-Jun. 

ATF-2 is a member of the ATF/CREB (cyclin AMP response element binding protein) family of transcription factors which associates with c-Jun to form the leucine-zipper hterodimer, c-Jun/ATF-2, that preferentially binds the TNFalppha promoter at the -106 to -99 bp site.

NK Activators: anisomycin

JNK inhibitors: SP600125 (Bennett et al., 2001)

p38 stress-activated protein kinases (p38SAPKs)

The p38SAPK pathway is involved in many aspects of immune cell function, being important in the innate immune response as well as in the adaptive immune response. In addition, p38SAPK may play an important role in T-cell development because it is found to be activated in T cells in the thymus. The cytokines IL-2 and IL-7 also activate p38SAPK in T cells. 

p38 is a master regulator of NF-kB recruitment to a subset of genes activated in cells exposed to inflammatory stimuli. Under one proposed model, NF-kB dimers translocated to the nucleus in response to stimulus bind to constitutively accessible NF-kB sites and contribute to the activation of these promoters. In some cases the p38 pathway, at least in part through the induction of H3 phosphorylation and phosphoacetylation, orchestrates the modifications that lead to enhanced accessibility of NF-kB sites. 

P38 stablizlies mRNA containing AU repeats, including genes that encode for TNF.

In some situations the p38 MAPK pathway appears to be needed for translation of an mRNA because blocking the pathway inhibits production of protein without causing disappearance of the mRNA. For example, blocking p38 MAPK in murine macrophages stimulated with LPS almost completely inhibits production of TNF? protein, but only partially inhibits induction of its mRNA. LPS also induces TNF? mRNA in the MAPKAPK-2 knockout mouse, but little or no protein is produced.

p38 Activator: Anisomycin 

P38 Inhibitors: SB-203580 (Alexis), SB202190

Regulation of MAPs

MAP kinases are themselves regulated by kinases and phosphatases, such as members of the MAP kinase phosphatase (MKP) family. MAPKs can be inactivated by removal of either their threonine or tyrosin phophates. A large number of phosphatases may be involved.

MAP involvement in Cancer immune evasion

MAPK signalling pathway can play a role in cancer immune evasion by augmenting the expression of the immunoregulatory cytokines IL-6 and IL-10. The impact of this signalling pathway on a tumour’s immunological status is particularly relevant in melanoma, where aobut half of tumours carry a mutation in the MAPK BRAF, the BRAF-V600E activating mutation, and wehre immune checkpoint blockage is a first line therapy.