The two-receptor system PAR-1/PAR-4 mediates α-thrombin-induced [Ca2+]i mobilization in human astrocytoma cells

Kaufmann, Roland; Patt, Stephan; Zieger, Michael; Kraft, Robert A.; Tausch, Svetlana; Henklein, Peter; Nowak, G

doi:10.1007/pl00008481

Cited by 31 publications

(19 citation statements)

References 14 publications

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“…The result of the literature review is summarized in Tables 1, 2, 3, and 4, (Arora et al 2008;Beaulieu and Church 2007;Bromberg et al 2001;Caruso et al 2006;Cooper et al 2003;Elzer et al 2008;Fujimoto et al 2006;Ghio et al 2006;Granovsky-Grisaru et al 2006;Hazarika et al 2004;Hjortoe et al 2004;Ikeda et al 2003Ikeda et al , 2006Jahan et al 2007;Jin et al 2003;Kang et al 2003;Kaufmann et al 1998Kaufmann et al , 1999Kaufmann et al , 2000Kim et al 2002;Massi et al 2005;Matej et al 2007;Miyata et al 2000;Mize et al 2008;Ohta et al 2003;Okamoto et al 2001;Radjabi et al 2008;Rudroff et al 2002;Sánchez-Hernández et al 2008;Seo et al 2007;Shibata et al 2004;Yoshii et al 2005;Zhang et al 2004). …”

Section: Resultsmentioning

confidence: 96%

Expression of proteinase-activated receptor 1-4 (PAR 1-4) in human cancer

Elste

Petersen

2010

J Mol Hist

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Proteinase activated receptors (PAR 1-4) are membrane receptors with a unique way of activation by proteinases like thrombin, trypsin and matrix metalloproteinases which lead to a specific cellular response. To evaluate the significance of expression and co-expression of PAR in cancer we performed a survey on published data. A Pubmed literature search on "PAR, thrombin, cancer" was performed and 46 publications were selected for systematic review based on the availability of information on tumor type, material type, detection method and specification of positive cases. PAR-1 was found in 77.3% of malignant samples (n = 678), PAR-2 in 79.5% (n = 592), PAR-3 in 12.6% (n = 87) and PAR-4 in 54.9% (n = 153). PAR-1 and -2 were present in adenocarcinomas, melanomas, osteosarcomas, glioblastomas, meningiomas, leukaemias and squamous cell carcinomas. Presence of PAR-3 was limited to kidney and liver cancer. The data on PAR-4 expression was inconclusive. Those studies analysing PAR-1 and PAR-2 reported coexpression of the two receptors. PAR-1 and -2 are widely expressed in human tumors suggesting an important role in tumorigenesis and providing potential targets for therapy. PAR-3 and PAR-4 are less frequently detectable, their expression and potential role in tumorigenesis require further investigation.

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Section: Resultsmentioning

confidence: 96%

Expression of proteinase-activated receptor 1-4 (PAR 1-4) in human cancer

Elste

Petersen

2010

J Mol Hist

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“…ing the physiology of PAR activation (Santulli et al, 1995;Faruqi et al, 2000;Kaufmann et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Thrombin elicits platelet activation by cleaving PAR-1 and PAR-4 in human (Kahn et al, 1999), as well as by cleaving PAR-3 and PAR-4 in mice (Kahn et al, 1998), raising the possibility that certain cellular consequences induced by thrombin in astrocytes may be regulated by PARs other than PAR-1. The tworeceptor system PAR-1/PAR-4 has also been found in human astrocytoma cells to mediate thrombin-induced [Ca 2ϩ ] i mobilization (Kaufmann et al, 2000). Considering that astrocytes are the major source of many of the neurotrophic factors known in the brain and contribute to the blood-brain barrier (Furukawa et al, 1986;Hatten et al, 1988;Janzer and Raff, 1987), and thrombin is involved mainly in inflammatory processes, these observations prompted us to explore whether PAR-3 and PAR-4 are co-expressed with PAR-1 and PAR-2 in astrocytes and, if present, whether they serve distinct functions.…”

Section: Introductionmentioning

confidence: 98%

Four subtypes of protease‐activated receptors, co‐expressed in rat astrocytes, evoke different physiological signaling

Wang

Ubl

Reiser

2001

Glia

168

147

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Protease-activated receptors (PARs) are newly identified members of the superfamily of G-protein-coupled receptors that initiate cell signaling by the proteolytic activity of extracellular serine proteases. Certain proteases are believed to be involved in development and repair processes and most likely regulate multiple functions of the CNS by activating PARs. Three members of this family (PAR-1, PAR-3, and PAR-4) are considered thrombin receptors, whereas PAR-2 is activated by trypsin. In the present study, using reverse transcription-polymerase chain reaction (RT-PCR), immunocytochemistry, and Ca(2+) mobilization studies, we demonstrate that PAR-1, PAR-2, PAR-3, and PAR-4 are functionally co-expressed in cultured rat astrocytes. Short-term stimulation of astrocytes with thrombin, trypsin, and peptides corresponding to the tethered ligand domains of PAR-1, PAR-2, PAR-3, and PAR-4 induced a transient rise of [Ca(2+)](i) in cultured astrocytes. In studying calcium signaling, based on receptor desensitization, and using an antagonist of thrombin receptor PAR-1, we provide evidence that the thrombin-induced [Ca(2+)](i) response in astrocytes in addition to PAR-1 stimulation, involves also stimulation of PAR-3 and PAR-4. Trypsin, in addition to PAR-2, can also activate PAR-1 and PAR-4. Furthermore we find that activation of PAR-1, and PAR-2 induces proliferation of astrocytes while PAR-4 activation exerts toxic effects. This study is the first to show that (1) cultured astrocytes functionally express PAR-3 and PAR-4 together with PAR-1 and PAR-2; (2) PAR-3-activating peptide (TFRGAP) is effective in eliciting Ca(2+) signaling; and (3) activation of different PARs leads to distinct downstream effects.

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“…For instance, a PAR 1 -PAR 4 two-receptor system has been demonstrated to mediate a closely related thrombin-induced signalling in both astrocytoma [138] and hepatocellular carcinoma [158] cells where PAR 1 and PAR 4 clusters could be detected by a high-resolution field emission scanning electron microscopy (FESEM) freeze-fracture replica immunolabeling technique. Although not accepted in general as a method to verify receptor dimerization, these data indicate structural proximity of PAR 1 and PAR 4 and therefore underline the need to evaluate the PAR dimerization concept in future studies of neoplastic cells.…”

Section: Receptor-receptor Interactions – a Critical Element In Par Smentioning

confidence: 99%

“…A PAR 1 /PAR 4 two-receptor system has been demonstrated to mediate a closely related thrombin-induced signalling and cell migration process in both astrocytoma [138] and hepatocellular carcinoma [158]. If this response can be shown to contribute to tumor progression/metastasis, it may be worth targeting the cancer with agents that disrupt the PAR 1 -PAR 4 interactions.…”

Section: Proteinase-activated Receptor Signalling Receptor Dimerizatmentioning

confidence: 99%

Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact

et al. 2013

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Proteinase-activated receptors (PARs) are a subfamily of G protein-coupled receptors (GPCRs) with four members, PAR1, PAR2, PAR3 and PAR4, playing critical functions in hemostasis, thrombosis, embryonic development, wound healing, inflammation and cancer progression. PARs are characterized by a unique activation mechanism involving receptor cleavage by different proteinases at specific sites within the extracellular amino-terminus and the exposure of amino-terminal “tethered ligand“ domains that bind to and activate the cleaved receptors. After activation, the PAR family members are able to stimulate complex intracellular signalling networks via classical G protein-mediated pathways and beta-arrestin signalling. In addition, different receptor crosstalk mechanisms critically contribute to a high diversity of PAR signal transduction and receptor-trafficking processes that result in multiple physiological effects.In this review, we summarize current information about PAR-initiated physical and functional receptor interactions and their physiological and pathological roles. We focus especially on PAR homo- and heterodimerization, transactivation of receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases (RSTKs), communication with other GPCRs, toll-like receptors and NOD-like receptors, ion channel receptors, and on PAR association with cargo receptors. In addition, we discuss the suitability of these receptor interaction mechanisms as targets for modulating PAR signalling in disease.

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The two-receptor system PAR-1/PAR-4 mediates α-thrombin-induced [Ca2+]i mobilization in human astrocytoma cells

Cited by 31 publications

References 14 publications

Expression of proteinase-activated receptor 1-4 (PAR 1-4) in human cancer

Expression of proteinase-activated receptor 1-4 (PAR 1-4) in human cancer

Four subtypes of protease‐activated receptors, co‐expressed in rat astrocytes, evoke different physiological signaling

Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact

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