IndraLab

"Upon extracellular activation by cellular stressors, such as oxidative stress or UV light, or stimulation with cytokines or growth factors, p38 MAPK activates MK2 (MAPK-activated protein kinase 2, MAPKAPK2) and the compensatory MK3 (MAPKAPK3) ( xref , xref )."

"However, p38 MAPK can also activate MK3 and MK5 [ xref ], suggesting that these protein kinases may also be implicated in stress-induced HSP27 phosphorylation."

"MK3 is the MAPKAPK that is most structurally related to MK2 and is also directly activated by p38 MAPK [ xref ]."

"This led to the development of a large number of p38 inhibitors, most of which target the p38α and β isoforms, although work with gene targeted mice has shown that in macrophages p38α, and not β, is the critical isoform for the regulation of TLR‐induced proinflammatory cytokine production. xref p38α is able to activate further downstream kinases, including MKs and MSKs, which can contribute to the ability of p38 to regulate cytokine production. xref While MK2 and MK3 are solely activated by p38 in vivo , MSK1 and the related kinase MSK2 are direct substrates for both p38α and ERK1/2. xref Work in macrophages has shown that MSKs induce anti‐inflammatory feedback pathways and are required for the production of IL‐10 by these cells. xref , xref Knockout of MK2 was found to reduce TNF production in response to TLR agonists both in vivo and in isolated macrophages. xref While MK2 appears to be the more dominant isoform, some compensation does exist between MK2 and MK3, as double knockout of both MK2 and MK3 resulted in a greater suppression of TNF production than knockout of MK2 alone following intraperitoneal injection of LPS in mice. xref In macrophages, the major mechanism by which MK2 and MK3 regulate the production of TNF is via phosphorylation of the mRNA‐binding protein TTP (also known as Zfp36). xref , xref TTP is an mRNA‐binding protein that recognizes AU‐rich elements in the 3′UTR of certain mRNAs including that of TNF. xref Once bound, TTP can both inhibit the translation of the mRNA and promote its degradation."

"MK2 and MK3 possess 75% sequence identity and are directly activated by p38 MAPK [ xref , xref ]."

"Whereas MK2 and MK3 are activated by p38 MAPK, MK5 has also been shown to be activated by ERK3 and ERK4."

"That is, the dose-dependent reduction in neuron killing by minocycline corresponded with a reduction in p38 mitogen-activated protein kinase activation in microglia; however, none of the Kv1.3 blockers affected p38 activation."

"P38α activates the downstream kinases MK2 and MK3 and in mast cells, MK2 and 3 are required for the p38α mediated regulation of TNF, IL-6, IL-13 and GM-CSF production by IL-33 ."

"IL‐33‐induced cytokine production requires the p38‐activated kinases MK2 and MK3."

"MAPK-activated kinases MK2 and MK3 are uniquely activated by p38 MAPK, whereas the mitogen- and stress-activated kinases MSK1 and MSK2 can be activated by either p38 MAPK or ERK."

"Using unbiased approaches, we identified Beclin 1 S90 as a key phosphorylation site in starvation-induced autophagy and identified two stress-activated protein kinase signaling pathway family members, the p38 MAPK-activated protein kinases MK2 and MK3, as crucial kinases that mediate Beclin 1 S90 phosphorylation."