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.

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Erk and p38 mapk-activated protein kinases: a family of protein kinases with diverse biological functions

This review is an account of recent advances in our understanding of the mechanisms of thrombus formation, with emphasis on two independent pathways: one involving primarily platelets and the other initiated by tissue factor.

/pdf/mechanisms-of-thrombus-formation-1ke77bbdis.pdf

Mechanisms of Thrombus Formation

Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibα and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features.

/pdf/monocytes-neutrophils-and-platelets-cooperate-to-initiate-v2uvv3reie.pdf

Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo

Cells are continuously exposed to a variety of environmental stresses and have to decide 'to be or not to be' depending on the types and strength of stress. Among the many signaling pathways that respond to stress, mitogen-activated protein kinase (MAPK) family members are crucial for the maintenance of cells. Three subfamilies of MAPKs have been identified: extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinases (JNKs), and p38-MAPKs. It has been originally shown that ERKs are important for cell survival, whereas JNKs and p38-MAPKs were deemed stress responsive and thus involved in apoptosis. However, the regulation of apoptosis by MAPKs is more complex than initially thought and often controversial. In this review, we discuss MAPKs in apoptosis regulation with attention to mouse genetic models and critically point out the multiple roles of MAPKs.

Mitogen-activated protein kinases in apoptosis regulation.

Cytokines act as pleiotropic polypeptides regulating inflammatory and immune responses through actions on cells. They provide important signals in the pathophysiology of a range of diseases, including diabetes mellitus. Chronic low-grade inflammation and activation of the innate immune system are closely involved in the pathogenesis of diabetes and its microvascular complications. Inflammatory cytokines, mainly IL-1, IL-6, and IL-18, as well as TNF-alpha, are involved in the development and progression of diabetic nephropathy. In this context, cytokine genetics is of special interest to combinatorial polymorphisms among cytokine genes, their functional variations, and general susceptibility to diabetic nephropathy. Finally, the recognition of these molecules as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.

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The Role of Inflammatory Cytokines in Diabetic Nephropathy

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1538-7836.2005.01236.x

Effects of factor IX or factor XI deficiency on ferric chloride‐induced carotid artery occlusion in mice

An optimized murine model of ferric chloride-induced arterial thrombosis for thrombosis research

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1538-7836.2006.02093.x

Effects of factor XI deficiency on ferric chloride-induced vena cava thrombosis in mice.

MEK1/2 is a serine/threonine protein kinase that phosphorylates and activates extracellular signal-responsive kinase (ERK)1/2. In the present study we explored the role of MEK1/2 in ischemic brain injury using a selective MEK1/2 inhibitor, SL327, in mice. C57BL/6 mice were subjected to a 30-min occlusion of the middle cerebral artery (MCAO) followed by reperfusion. Western blot analysis demonstrated the immediate activation of MEK/ERK after reperfusion (within the first 10 min) in the ischemic brain; this activation was dose dependently blocked by SL327 (10-100 mg/kg, i.p.). A single dose of SL327 (100 mg/kg) administered 15 min before or 25 min after the onset of ischemia resulted in 63.6% (n = 18, p < 0.001) and 50.7% (n = 18, p < 0.01) reduction in infarct size, respectively, compared with vehicle-treated mice. Similarly, SL327 significantly reduced neurological deficits 1 to 3 days after reperfusion (n = 12, p < 0.01). The salutary effect of SL327-induced neuroprotection was independent of mitochondrial cytochrome c release or caspase-8-mediated apoptosis; however, SL327 markedly suppressed the levels of active caspase-3 and DNA fragmentation (as a measure of apoptosis) after ischemia/reperfusion. Our data suggest that the inhibition of MEK1/2 results in neuroprotection from reperfusion injury and that this protection may be associated with the reduction in apoptosis.

Significant neuroprotection against ischemic brain injury by inhibition of the MEK1 protein kinase in mice: exploration of potential mechanism associated with apoptosis.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1538-7836.2006.01703.x

Xinkang Wang

Papers

Effects of factor IX or factor XI deficiency on ferric chloride‐induced carotid artery occlusion in mice

An optimized murine model of ferric chloride-induced arterial thrombosis for thrombosis research

Effects of factor XI deficiency on ferric chloride-induced vena cava thrombosis in mice.

Significant neuroprotection against ischemic brain injury by inhibition of the MEK1 protein kinase in mice: exploration of potential mechanism associated with apoptosis.

Murine model of ferric chloride-induced vena cava thrombosis: evidence for effect of potato carboxypeptidase inhibitor.