Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1

Jeffrey, Kate L.; Brummer, Tilman; Rolph, Michael S.; Liu, Sue Min; Callejas, Nuria A.; Grumont, Raelene J.; Gilliéron, Corine; Mackay, Fabienne; Grey, Shane T.; Camps, Montserrat; Rommel, Christian; Gerondakis, Steve; Mackay, Charles R.

doi:10.1038/ni1310

Cited by 229 publications

(275 citation statements)

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“…A negative crosstalk between the JNK and ERK pathways has been found in TNFα-stimulated cells, in which prolonged JNK phosphorylation uncouples MEK-mediated ERK activation in a c-Jun-dependent manner (Shen et al, 2003). Remarkably, this negative feedback was found in DUSP2-null macrophages and was proposed as an explanation for the reduced inflammatory cytokine expression in these cells (Jeffrey et al, 2006). One of the MAPK crosstalk mechanisms is the suppressive effect of p38α on JNK activation.…”

Section: Crosstalk Between Mapk Signaling In Inflammation and Cancermentioning

confidence: 89%

“…In addition, DUSP1-deficient mice show high susceptibility to LPSinduced septic shock and collagen-induced arthritis (Lang et al, 2006). Interestingly, DUSP2-deficient macrophages produce attenuated levels of inflammatory mediators, probably due to a negative feedback from the prolonged JNK activation on ERK in these cells (Jeffrey et al, 2006). Until now, studies on DUSP functions in cancer development have mainly involved expression analyses of clinical tumor samples (Keyse, 2008).…”

Section: Perspectivesmentioning

confidence: 99%

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MAPK signaling in inflammation-associated cancer development

2010

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Mitogen-activated protein (MAP) kinases comprise a family of protein-serine/threonine kinases, which are highly conserved in protein structures from unicellular eukaryotic organisms to multicellular organisms, including mammals. These kinases, including ERKs, JNKs and p38s, are regulated by a phosphorelay cascade, with a prototype of three protein kinases that sequentially phosphorylate one another. MAPKs transduce extracellular signals into a variety of cellular processes, such as cell proliferation, survival, death, and differentiation. Consistent with their essential cellular functions, MAPKs have been shown to play critical roles in embryonic development, adult tissue homeostasis and various pathologies. In this review, we discuss recent findings that reveal the profound impact of these pathways on chronic inflammation and, particularly, inflammation-associated cancer development.

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Section: Crosstalk Between Mapk Signaling In Inflammation and Cancermentioning

confidence: 89%

Section: Perspectivesmentioning

confidence: 99%

MAPK signaling in inflammation-associated cancer development

2010

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“…For detailed methods refer to SI Material and Methods. Briefly, bone marrow-derived mast cells (BMMCs) were isolated from femurs and tibias of adult wild-type and mutant mice and cultured in the presence of 10 ng/mL recombinant mouse IL-3 (PreProtech) for 4 -9 weeks at 37°C in 5% CO2 to allow for the differentiation of differentiation of BMMCs (41). For co-cultures, BMMCs (1 ϫ 10 4 cell/mL) were added to 5-day-old dissociated DRG cultures and incubated in supplemented Hams F-12 medium including 10 ng/mL IL-3.…”

Section: Drg Neuron Culturementioning

confidence: 99%

Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation

Folgueras

Valdés-Sánchez²,

Llano³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Peripheral interactions between nociceptive fibers and mast cells contribute to inflammatory pain, but little is known about mechanisms mediating neuro-immune communication. Here we show that metalloproteinase MT5-MMP (MMP-24) is an essential mediator of peripheral thermal nociception and inflammatory hyperalgesia. We report that MT5-MMP is expressed by CGRP-containing peptidergic nociceptors in dorsal root ganglia and that Mmp24-deficient mice display enhanced sensitivity to noxious thermal stimuli under basal conditions. Consistently, mutant peptidergic sensory neurons hyperinnervate the skin, a phenotype that correlates with changes in the regulated cleavage of the cell-cell adhesion molecule N-cadherin. In contrast to basal nociception, Mmp24 ؊/؊ mice do not develop thermal hyperalgesia during inflammation, a phenotype that appears associated with alterations in N-cadherin-mediated cell-cell interactions between mast cells and sensory fibers. Collectively, our findings demonstrate an essential role of MT5-MMP in the development of dermal neuro-immune synapses and suggest that this metalloproteinase may be a target for pain control.inflammation ͉ mast cell ͉ N-cadherin

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“…Finally, PAC-1 (DUSP2)-deficient mice also develop normally but are protected from arthritis, similar to MKP-5-deficient mice (34). However, the signaling mechanisms of Pac-1 regulation is complex since, although there is enhanced JNK1 activity, p38 MAPK and Erk are paradoxically decreased (34). These results suggest that the enhanced activity of JNK influences p38 MAPK/Erk activities in a cross-talk type of manner (34) Noonan syndrome through constitutive stimulation of the Ras/Erk pathway (7).…”

Section: Shp-1 and Shp-2: Opposites Attractmentioning

confidence: 99%

“…Hence, although MKP-5 and MKP-1 both target JNK, the physiological outcome of MKP-5 deletion suggests that MKP-5 and MKP-1 have distinct regulatory roles even within the immune system. Finally, PAC-1 (DUSP2)-deficient mice also develop normally but are protected from arthritis, similar to MKP-5-deficient mice (34). However, the signaling mechanisms of Pac-1 regulation is complex since, although there is enhanced JNK1 activity, p38 MAPK and Erk are paradoxically decreased (34).…”

Section: Shp-1 and Shp-2: Opposites Attractmentioning

confidence: 99%

Physiological Signaling Specificity by Protein Tyrosine Phosphatases

Soulsby

Bennett

2009

Physiology

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Intracellular signaling pathways that are mediated by tyrosyl phosphorylation are controlled through the balanced and opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). The view that PTPs are equal contributing partners in the regulation of cellular tyrosyl phosphorylation continues to mature. However, there still remains the perception that PTPs play largely housekeeping roles. A growing body of evidence firmly dispels this perception, and it is evident that PTPs function with stringent signaling specificity, in concert with their PTK counterparts, to define specific biological outcomes. In this review, we will focus on illustrating that PTPs exhibit defined substrate specificity and subsequently regulate signaling pathways in a precise manner. The PTP SuperfamilyThe superfamily of PTPs is characterized by a consensus signature motif represented by HC(X) 5 R, which defines the active site of these enzymes. Two classes of PTPs can be defined (FIGURE 1). The first class is composed of classical PTPs that are defined by cysteine-based phosphotyrosine specificity, and the second class constitutes the dual-specificity phosphatases (DSPs). There are 37 classical human PTP genes that contain at least one PTP domain of ~280 amino acids. The DSPs are much larger in number, and there are 65 of these genes in the human genome. The classical PTP genes can be further subdivided into transmembrane receptor PTPs (RPTPs), or non-transmembrane PTPs, which localize to the cytoplasm (2, 4, 68). There are 12 RPTPs containing tandem PTP domains with the remainder containing a single PTP domain. The membrane-proximal PTP domain (D1) and membrane-distal PTP domain (D2) serve distinct roles. In the majority of cases, the D1 PTP domain comprises the active domain, whereas in most cases, but not all, the D2 domain serves a negative regulatory role. Although still quite controversial, evidence has been put forth to suggest that RPTPs are regulated through dimerization whereby RPTP activity is inhibited upon dimerization. However, there is also evidence against such a model of RPTP regulation, and further work in this particular area is warranted. Much like the RTKs, RPTPs utilize their diverse extracellular domains to transduce intracellular signals through binding to soluble ligands, but, in addition, RPTPs utilize their extracellular domains to mediate cell-cell and cell-matrix interactions (33,35,45,73). The nontransmembrane or cytoplasmic PTPs contain a single PTP domain, and their diversity is derived through noncatalytic regulatory domains that reside either at the NH 2 or COOH terminus of the PTP domain (2-3, 68). The noncatalytic domains are critical for exerting PTP substrate specificity and include one or more of the following features: 1) regulation of PTP activity, 2) directing subcellular localization, and 3) targeting PTP protein-protein interactions. Hence, the noncatalytic regions of the non-transmembrane PTPs offer a broad level of structural diversity, and together with the PTP...

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Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1

Cited by 229 publications

References 50 publications

MAPK signaling in inflammation-associated cancer development

MAPK signaling in inflammation-associated cancer development

Metalloproteinase MT5-MMP is an essential modulator of neuro-immune interactions in thermal pain stimulation

Physiological Signaling Specificity by Protein Tyrosine Phosphatases

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