Mitogen-activated protein kinase (MAPK)

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MAPKAt a molecular level, the immune state is controlled through an exhaustive array of interconnected and tightly controlled series of intracellular signaling pathways (1, 2). This is achieved, in part, by activating or deactivating regulatory proteins through protein phosphorylation. The highly conserved mitogen-activated protein kinase (MAPK) family is one of the major kinase families that regulate cells by transducing extracellular signals into cellular responses (3). Three important members of this family are the extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). Each is similarly activated by dual phosphorylation on adjacent threonine and tyrosine residues.The classic MAPK cascade consists of three sequential intracellular protein kinase activation steps and is initiated when the first member, MAPK kinase kinase (MAPKKK), is activated (Fig. 1). MAPKKK is a protein kinase that phosphorylates and activates MAPK kinase (MAPKK), and this activation is followed by activation of the specific MAPK. MAPKs are proline-directed protein kinases, meaning that they phosphorylate serine or threonine residues that are neighbors to proline. In this manner, MAPKs activate numerous protein kinases, nuclear proteins, and transcription factors, leading to downstream signal transduction. Activation of the MAPK cascade is rapid and enables cells to respond to environmental changes in a regulated fashion.Erk.ERK was the first identified of all the MAPK family members. ERK is made up of two isoforms, ERK1 and ERK2, and is commonly referred to as ERK 1/2. ERK is primarily involved in proliferation, transformation, and differentiation. ERK activation is initiated by the phosphorylation and activation of Raf (MAPKKK), followed by the phosphorylation and activation of MEK 1/2 (MAPKK) that leads to the activation of ERK 1/2 (MAPK) (4). Raf is a highly conserved kinase that is activated by the G-protein, Ras. Ras is activated through interaction with Grb2-SOS complex, where SOS catalyzes the formation of Ras-guanosine triphosphate (GTP) complex. This GTP-bound complex binds to Raf and activates it in a calcium-dependent manner (5). This cascade is activated by a number of mitogens, including epidermal growth factor, platelet-derived growth factor, thromboxane A2, angiotensin II, transforming growth factor β, and insulin (6). Additionally, ERK is activated in response to endotoxin, oxidative stress, platelet activating factor (PAF), and adherence by innate immune system cells such as monocytes and macrophages. Activation of ERK by oxidative stress, PAF, and adherence is important in monocyte/macrophage proinflammatory reprogramming, characteristic of sepsis, by modulating the activation status of the regulatory kinase calcium/calmodulin-dependent protein kinase II (CaMK II), leading to dysregulated inflammatory cytokine production (7).p38.p38 is an important MAPK member that is activated in response to physiologic stress, endotoxin, osmotic stress, and ultraviolet exposure (8). Five isoforms of the p38 group have been identified: p38α (SAPK2), p38β, p38β2, p38γ (SAPK3), and p38δ (9). Expression of these isoforms varies among tissues. p38α is highly expressed in leukocytes and bone marrow, p38β is expressed in heart and brain, and p38γ is expressed predominately in skeletal muscles. Similar to ERK, p38 is activated by a series of upstream activators. The two major upstream activators are MKK3 and MKK6. MKK6 is poorly expressed in leukocytes, whereas MKK3 is highly expressed in leukocytes. More proximally, there are multiple diverse kinases that act as MAPKKK for this pathway, including TAK1 and AK-1. This diverse array of proximal kinases allows for activation by a wide range of stimuli.Major substrates for p38 include MAP kinase–activated protein kinase-2 (MAPKAP-K2) and MAPKAP-K3. MAPKAP-K2/3 are serine protein kinases known to subsequently activate heat shock protein-27 (HSP-27) (10).

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