Abstract
The G protein-coupled receptor proteinase-activated receptor 2 (PAR2) has been implicated in various aspects of cellular physiology including inflammation, obesity and cancer. In cancer, it usually acts as a driver of cancer progression in various tumor types by promoting invasion and metastasis in response to activation by serine proteinases. Recently, we discovered another mode through which PAR2 may enhance tumorigenesis: crosstalk with transforming growth factor-β (TGF-β) signaling to promote TGF-β1-induced cell migration/invasion and invasion-associated gene expression in ductal pancreatic adenocarcinoma (PDAC) cells. In this chapter, we review what is known about the cellular TGF-β responses and signaling pathways affected by PAR2 expression, the signaling activities of PAR2 required for promoting TGF-β signaling, and the potential molecular mechanism(s) that underlie(s) the TGF-β signaling–promoting effect. Since PAR2 is activated through various serine proteinases and biased agonists, it may couple TGF-β signaling to a diverse range of other physiological processes that may or may not predispose cells to cancer development such as local inflammation, systemic coagulation and pathogen infection.
Highlights
Late-stage pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are non-curable diseases with a poor prognosis
We focus on one aspect of this signaling crosstalk, the impact of tumor cell and stromal cell-expressed proteinase-activated receptor 2” (PAR2) expression on transforming growth factor-β (TGF-β) signaling and TGF-β-mediated cellular responses in PDAC-derived cancer cells and HCC-derived cancer and stromal cells
If one considers that numerous studies provide evidence for PAR2 transactivation of epidermal growth factor receptor (EGFR), VEGFR, platelet-derived growth factor receptor (PDGFR) and MET, it seems quite likely that TGF-β1/activin receptor-like kinase 5” (ALK5) and PAR2 can cooperatively signal via these RTKs
Summary
Late-stage pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are non-curable diseases with a poor prognosis. Despite marked differences in their pathological features—PDAC are stromal-predominant, fibrotic/desmoplastic, poorly vascularized tumors, whereas HCC are cellular and highly vascularized—PDAC and HCC share the G protein-coupled receptor “proteinase-activated receptor 2” (PAR2) and transforming growth factor-β (TGF-β) as key factors involved in primary tumor growth and cancer cell invasion and metastasis. 2.1P.APARR22isSiagnparliontgotype member of a subfamily of G protein-coupled receptors, the proteinaseactivated receptors (PARs) that comprise PAR1, PAR3 and PAR4. These receptors regulate a varietPyAoRf 2phisysaioplorogtioctaylpperomceesmsebsersuocfhaassuvbafsaomrielgyuolaf tGionp,rnooteciinc-ecpotuiopnle,dinrfleacmepmtoartsi,otnhe[1p–4ro] taesinwaseell- as a navucamtriivebateytreodoffrppehcayetpshitooollroosgg(iicPeasAliRpnsrco)luctehdsaisntegsalstsuioscshcuoaemsfipvbrarissooesriePsgA[u5Rl]a1at,inoPdnA,cRna3onccaiecnredp[6tPi–oA1nR3,]4i.n. PfTlAahmRessmeaarrteeicoaenpct[t1iov–ra4st]eraedsgbwuylealstleearasine proateniunmasbee-rmoef dpiaattheodlocglieeasviangcleuodfintghetisesxuterafciberlolusilsar[5N] a-tnedrmcainncuesr r[6e–s1u3lt].inPgAiRns eaxrepoacstuivreatoedf aby“tseetrhineered ligapnrodt”eitnhaasteb-mineddsiatotetdheclreeacveapgteoroaf nthdeaecxtitvraacteeslluitla[1r,2N]-(tFerigmuirneu1s).reEsauclhtinogf tihneefxopuorsPuAreRosfisa a“ctteitvhaetreeddby a slpigeacinfidc”tthhoaut gbhinodvsetrolathpepirnegcespettorofansedriancetivpartoetseiint a[1s,e2s] ((FFiigguurree 11)). EEaachchmmemembebreorfothf ethfaemfailmy,iPlyA, RPA1,RP1A,RP2A, RPA2,RP3AaRnd PanAdR4P,AisR4, is aaccttiivvaatteedd bbyy tthheeiinnddiiccaatteeddsseerirnineepprortoetieniansaesse(sin(ignrgeyre).yA).ltAerltneartnivaetilvye, leya,cehaPchARPAmRaymbaeyabcetivaactteivdaitneda in a ccleleaavvaaggee--iinnddeeppeennddeenntt mmaannnneerrbbyyppeepptitdideesseeqquuenencecses(b(obxoexdedininrerde)df)rformomitsittsettehtehreerdedliglaignadnrdegreiognion (re(dreldinleisneins itnhethceacratortoononatatthtehetotpop).)
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