Cathepsins are an essential protease family in all living cells. The cathepsins play an essential roles such as protein catabolism and protein synthesis. To targeting to various organella and to regulate their activity, the post translational-processing and modification play an important role Cathepsins are translated in polysome as the pre-pro-mature forms. The pre-peptide is removed cotranslationally and then translocated to Golgi-apparatus and the pro-part is removed and the mature-part is glycosylated, and the mature-part is targeted into the lysosome mediated by mannose-6-phosphate signal and the mature-part is bound with their coenzymes. The degradation of the mature-part is started by the limited proteolysis of the ordered nicked bonds to make hydrophobic peptides. The peptides are incorporated into phagosome or proteasome after ubiquitinated and are degrade into amino-acids. Cystatins are endogenous inhibitors of cathepsins. 
Cystatin <i>&#x3b1;</i> which is only located in skin is phosphorylated at the near C-terminus by protein kinase-C, and the phosphorylate-cystatin <i>&#x3b1;</i> is incorporated into cornified envelope and conjugated with filaggrin-fiber by transglutaminase to form the linker-fiber of skin. The cystatin <i>&#x3b1;</i> is modified by glutathione or make their dimmer, and they are inactive. Those modifications are regulated by the redox-potential by the glutathione.

Nobuhiko Katunuma

Posttranslational Processing and Modification of Cathepsins and Cystatins

The descending pain modulatory system is thought to undergo plastic changes following peripheral tissue injury and exerts bidirectional (facilitatory and inhibitory) influence on spinal nociceptive transmission. The mitogen-activated protein kinases (MAPKs) superfamily consists of four main members: the extracellular signal-regulated protein kinase1/2 (ERK1/2), the c-Jun N-terminal kinases (JNKs), the p38 MAPKs, and the ERK5. MAPKs not only regulate cell proliferation and survival but also play important roles in synaptic plasticity and memory formation. Recently, many studies have demonstrated that noxious stimuli activate MAPKs in several brain regions that are components of descending pain modulatory system. They are involved in pain perception and pain-related emotional responses. In addition, psychophysical stress also activates MAPKs in these brain structures. Greater appreciation of the convergence of mechanisms between noxious stimuli- and psychological stress-induced neuroplasticity is likely to lead to the identification of novel targets for a variety of pain syndromes.

Hiroki Imbe

Emiko Senba

Akihisa Kimura

Tomohiro Donishi

Isao Yokoi

Yoshiki Kaneoke

Activation of Mitogen-Activated Protein Kinase in Descending Pain Modulatory System

In many cell types, growth factor removal induces the release of cytochrome-c from mitochondria that leads to activation of caspase-9 in the apoptosome complex. Here, we show that sustained stimulation of the Raf-1/MAPK1,3 pathway prevents caspase-9 activation induced by serum depletion in CCL39/<svg style="vertical-align:-0.0pt;width:11.4125px;" id="M1" height="10.6625" version="1.1" viewBox="0 0 11.4125 10.6625" width="11.4125"  xmlns="http://www.w3.org/2000/svg">
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</svg>Raf-1:ER fibroblasts. The protective effect mediated by Raf-1 is sensitive to MEK inhibition that is sufficient to induce caspase-9 cleavage in exponentially growing cells. Raf-1 activation does not inhibit the release of cytochrome-c from mitochondria while preventing caspase-9 activation. Gel filtration chromatography analysis of apoptosome formation <i  >in cells</i> shows that Raf-1/MAPK1,3 activation does not interfere with APAF-1 oligomerization and recruitment of caspase 9. Raf-1-mediated caspase-9 inhibition is sensitive to emetine, indicating that the protective mechanism requires protein synthesis. However, the Raf/MAPK1,3 pathway does not regulate XIAP. Taken together, these results indicate  that the Raf-1/MAPK1,3 pathway controls an apoptosis regulator that prevents caspase-9 activation in the apoptosome complex.

S&#233;bastien Cagnol

Anna Mansour

Ellen Van Obberghen-Schilling

Jean-Claude Chambard

Raf-1 Activation Prevents Caspase 9 Processing Downstream of Apoptosome Formation

Mycoparasitic <i  >Trichoderma</i> spp. act as potent biocontrol agents against a number of plant pathogenic fungi, whereupon the mycoparasitic attack includes host recognition followed by infection structure formation and secretion of lytic enzymes and antifungal metabolites leading to the host's death. Host-derived signals are suggested to be recognized by receptors located on the mycoparasite's cell surface eliciting an internal signal transduction cascade which results in the transcription of mycoparasitism-relevant genes. 
Heterotrimeric G proteins of fungi transmit signals originating from G-protein-coupled receptors mainly to the cAMP and the MAP kinase pathways resulting in regulation of downstream effectors. Components of the G-protein signaling machinery such as G<svg style="vertical-align:-0.1254pt;width:8.9375px;" id="M1" height="7.1750002" version="1.1" viewBox="0 0 8.9375 7.1750002" width="8.9375"  xmlns="http://www.w3.org/2000/svg">
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</svg> subunits and G-protein-coupled receptors were recently shown to play crucial roles in <i  >Trichoderma</i> mycoparasitism as they govern processes such as the production of extracellular cell wall lytic enzymes, the secretion of antifungal metabolites, and the formation of infection structures.

Markus Omann

Susanne Zeilinger

How a Mycoparasite Employs G-Protein Signaling: Using the Example of <i>Trichoderma</i>

Oral mucosal inflammatory responses to periodontopathic bacterium, <i>P. gingivalis</i>, and its key virulence factor, LPS, are characterized by a massive rise in epithelial cell apoptosis and the disturbances in NO signaling pathways.  Here, we report that the LPS-induced enhancement in rat sublingual salivary gland acinar cell apoptosis and NO generation was associated with the suppression in constitutive nitric oxide synthase (cNOS) activity and a marked increase in the activity of inducible nitric oxide synthase (iNOS). We demonstrate that the detrimental effect of the LPS on cNOS was manifested by the enzyme protein S-nitrosylation, that was susceptible to inhibition by iNOS inhibitor, 1400&#x2009;W.  Further, we show that a peptide hormone, ghrelin, countered the LPS-induced changes in apoptosis and cNOS activity. This effect of ghrelin was reflected in the decrease in cNOS S-nitrosylation and the increase in phosphorylation. Our findings imply that <i>P. gingivalis</i>-induced disturbances in the acinar cell NO signaling pathways result from upregulation in iNOS-derived NO that causes cNOS S-nitrosylation that interferes with its activation through phosphorylation.  We also show that ghrelin protection against <i>P. gingivalis</i>-induced disturbances involves cNOS activation associated with a decrease in its S-nitrosylation and the increase in phosphorylation.

Bronislaw L. Slomiany

Amalia Slomiany

Suppression by Ghrelin of <i>Porphyromonas gingivalis</i>-Induced Constitutive Nitric Oxide Synthase S-Nitrosylation and Apoptosis in Salivary Gland Acinar Cells

(GIMAPs) GTPase of the immunity associated protein family are a novel protein family of putative small GTPases. GIMAPs are mainly expressed in the cells of the immune system and have been associated with immunological functions, such as thymocyte development, apoptosis of peripheral lymphocytes and T helper cell differentiation. GIMAPs have also been linked to immunological diseases, such as T cell lymphopenia, leukemia and autoimmune diseases. In this review we examine the role of GIMAP proteins in T-lymphocyte biology.

Sanna Fil&#233;n

Riitta Lahesmaa

GIMAP Proteins in T-Lymphocytes

Inflammation plays a critical role in the development of cancer.  Matrix Metalloproteinase (MMP) functions in the remodeling of the extracellular matrix that is integral for many normal and pathological processes such as morphogenesis, angiogenesis, tissue repair, and tumor invasion.  The tissue inhibitor of metalloproteinases (TIMPs) family regulates the activity of multifunctional metalloproteinases. In this paper, we discuss the role and mechanism of MMP and TIMP in regulating inflammation responses in solid tumors.  We discuss the mechanism of MMP and inflammation in melanoma, colon cancer, breast cancer, and prostate cancer. We highlight the roles of the TIMP-2 in modulating the proinflammatory NF-<svg     style="vertical-align:-0.1638pt;width:8.7375002px;" id="M1" height="7.9499998" version="1.1" viewBox="0 0 8.7375002 7.9499998" width="8.7375002"  xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg">
	
		
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</svg>B pathway in melanoma and lung caner cells. Based on the molecular mechanisms of TIMPs and MMPs in inflammation and cancer, we can design new strategies for cancer therapy.

Jun Sun

Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases Are Essential for the Inflammatory  Response in Cancer Cells

The synthetic Vitamin A analog fenretinide is a promising chemotherapeutic agent. In the current paper, the role of PKC <svg style="vertical-align:-0.13794pt;width:7.9875002px;" id="M2" height="10.7375" version="1.1" viewBox="0 0 7.9875002 10.7375" width="7.9875002"  xmlns="http://www.w3.org/2000/svg">
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</svg> was examined in fenretinide-induced apoptosis in lymphoid leukemia cells. Levels of proapoptotic cleaved PKC <svg style="vertical-align:-0.13794pt;width:7.9875002px;" id="M3" height="10.7375" version="1.1" viewBox="0 0 7.9875002 10.7375" width="7.9875002"  xmlns="http://www.w3.org/2000/svg">
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</svg> positively correlated with drug sensitivity. Fenretinide promoted reactive oxygen species (ROS) generation. The antioxidant Vitamin C prevented fenretinide-induced PKC <svg style="vertical-align:-0.13794pt;width:7.9875002px;" id="M4" height="10.7375" version="1.1" viewBox="0 0 7.9875002 10.7375" width="7.9875002"  xmlns="http://www.w3.org/2000/svg">
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</svg> cleavage and protected cells from fenretinide. Suppression of PKC <svg style="vertical-align:-0.13794pt;width:7.9875002px;" id="M5" height="10.7375" version="1.1" viewBox="0 0 7.9875002 10.7375" width="7.9875002"  xmlns="http://www.w3.org/2000/svg">
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</svg> expression by shRNA sensitized cells to fenretinide-induced apoptosis possibly by a mechanism involving ROS production. A previous study demonstrated that fenretinide promotes degradation of antiapoptotic MCL-1 in ALL cells via JNK. Now we have found that fenretinide-induced MCL-1 degradation may involve PKC <svg style="vertical-align:-0.13794pt;width:7.9875002px;" id="M6" height="10.7375" version="1.1" viewBox="0 0 7.9875002 10.7375" width="7.9875002"  xmlns="http://www.w3.org/2000/svg">
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</svg> as cleavage of the kinase correlated with loss of MCL-1 even in cells when JNK was not activated. These results suggest that PKC <svg style="vertical-align:-0.13794pt;width:7.9875002px;" id="M7" height="10.7375" version="1.1" viewBox="0 0 7.9875002 10.7375" width="7.9875002"  xmlns="http://www.w3.org/2000/svg">
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</svg> may play a complex role in fenretinide-induced apoptosis and may be targeted in antileukemia strategies that utilize fenretinide.

Vivian R. Ruvolo

Kul B. Karanjeet

Todd F. Schuster

Rhoderick Brown

Yibin Deng

Edward Hinchcliffe

Peter P. Ruvolo

Role for PKC<svg style="vertical-align:-0.1638pt" height="12.4375" version="1.1" viewBox="0 0 8.9125004 12.4375" width="8.9125004" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,12.162)"><path id="x1D6FF" d="M494 514l-10 -15q-56 76 -106.5 117t-110.5 41q-45 0 -45 -30q0 -28 109 -152q59 -68 86 -118.5t27 -107.5q0 -62 -29.5 -119.5t-86.5 -96.5q-64 -45 -138 -45q-76 0 -121.5 53t-45.5 136q0 74 40.5 135t98.5 95q43 26 87 42q-40 59 -57.5 92t-17.5 62q0 46 39 77.5&#xA;t90 31.5q54 0 97.5 -35.5t65 -78.5t28.5 -84zM359 234q0 84 -90 191q-47 -17 -74 -47q-81 -89 -81 -200q0 -71 32.5 -109.5t72.5 -38.5q47 0 80 33t46.5 77.5t13.5 93.5z" /></g></svg> in Fenretinide-Mediated Apoptosis in Lymphoid Leukemia Cells

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Journal of Signal Transduction