Volume 9 Issue 1
Feb.  2023
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Haonan Yu, Zhihua Liu. GNA12 regulates C5a-induced migration by downregulating C5aR1-PLCβ2-PI3K-AKT-ERK1/2 signaling. Biophysics Reports, 2023, 9(1): 33-44. doi: 10.52601/bpr.2023.230001
Citation: Haonan Yu, Zhihua Liu. GNA12 regulates C5a-induced migration by downregulating C5aR1-PLCβ2-PI3K-AKT-ERK1/2 signaling. Biophysics Reports, 2023, 9(1): 33-44. doi: 10.52601/bpr.2023.230001

GNA12 regulates C5a-induced migration by downregulating C5aR1-PLCβ2-PI3K-AKT-ERK1/2 signaling

doi: 10.52601/bpr.2023.230001
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  • Corresponding author: zhihualiu@mail.tsinghua.edu.cn (Z. Liu)
  • Received Date: 12 January 2023
  • Accepted Date: 21 February 2023
  • Available Online: 06 May 2023
  • Publish Date: 28 February 2023
  • Gna12 has been identified as one of the reported inflammatory bowel disease (IBD) susceptibility genes in genome-wide association studies (GWAS). However, the function of GNA12 in intestinal homeostasis remains unknown. Here we report that GNA12, a G-protein α subunit, regulates C5a-induced migration in macrophages. Deficiency of GNA12 results in enhanced migration induced by C5a in macrophages. Mechanistically, GNA12 suppresses C5a-induced migration by downregulating the C5aR1-PLCβ2-PI3K-AKT-ERK1/2 signaling. Therefore, our study reveals that GNA12 is an anti-inflammatory factor, which might alleviate the development of inflammation by inhibiting the excessive chemotactic migration of macrophages.

  • Haonan Yu and Zhihua Liu declare that they have no conflict of interest.
    All institutional and national guidelines for the care and use of laboratory animals were followed.

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  • Akhshi TK, Wernike D, Piekny A (2014) Microtubules and actin crosstalk in cell migration and division. Cytoskeleton (Hoboken) 71(1): 1−23 doi: 10.1002/cm.21150
    Anderson CA, Boucher G, Lees CW, Franke A, D'Amato M, Taylor KD, Lee JC, Goyette P, Imielinski M, Latiano A, Lagace C, Scott R, Amininejad L, Bumpstead S, Baidoo L, Baldassano RN, Barclay M, Bayless TM, Brand S, Buning C, Colombel JF, Denson LA, De Vos M, Dubinsky M, Edwards C, Ellinghaus D, Fehrmann RS, Floyd JA, Florin T, Franchimont D, Franke L, Georges M, Glas J, Glazer NL, Guthery SL, Haritunians T, Hayward NK, Hugot JP, Jobin G, Laukens D, Lawrance I, Lemann M, Levine A, Libioulle C, Louis E, McGovern DP, Milla M, Montgomery GW, Morley KI, Mowat C, Ng A, Newman W, Ophoff RA, Papi L, Palmieri O, Peyrin-Biroulet L, Panes J, Phillips A, Prescott NJ, Proctor DD, Roberts R, Russell R, Rutgeerts P, Sanderson J, Sans M, Schumm P, Seibold F, Sharma Y, Simms LA, Seielstad M, Steinhart AH, Targan SR, van den Berg LH, Vatn M, Verspaget H, Walters T, Wijmenga C, Wilson DC, Westra HJ, Xavier RJ, Zhao ZZ, Ponsioen CY, Andersen V, Torkvist L, Gazouli M, Anagnou NP, Karlsen TH, Kupcinskas L, Sventoraityte J, Mansfield JC, Kugathasan S, Silverberg MS, Halfvarson J, Rotter JI, Mathew CG, Griffiths AM, Gearry R, Ahmad T, Brant SR, Chamaillard M, Satsangi J, Cho JH, Schreiber S, Daly MJ, Barrett JC, Parkes M, Annese V, Hakonarson H, Radford-Smith G, Duerr RH, Vermeire S, Weersma RK, Rioux JD (2011) Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet 43(3): 246−252 doi: 10.1038/ng.764
    Andreeva AV, Kutuzov MA, Voyno-Yasenetskaya TA (2008) G alpha12 is targeted to the mitochondria and affects mitochondrial morphology and motility. FASEB J 22(8): 2821−2831 doi: 10.1096/fj.07-104224
    Arthofer E, Hot B, Petersen J, Strakova K, Jager S, Grundmann M, Kostenis E, Gutkind JS, Schulte G (2016) WNT stimulation dissociates a frizzled 4 inactive-state complex with Galpha12/13. Mol Pharmacol 90(4): 447−459 doi: 10.1124/mol.116.104919
    Chiou WF, Tsai HR, Yang LM, Tsai WJ (2004) C5a differentially stimulates the ERK1/2 and p38 MAPK phosphorylation through independent signaling pathways to induced chemotactic migration in RAW264.7 macrophages. Int Immunopharmacol 4(10-11): 1329-1341
    Coffer PJ, Schweizer RC, Dubois GR, Maikoe T, Lammers JW, Koenderman L (1998) Analysis of signal transduction pathways in human eosinophils activated by chemoattractants and the T-helper 2-derived cytokines interleukin-4 and interleukin-5. Blood 91(7): 2547−2557 doi: 10.1182/blood.V91.7.2547
    Dobashi A (2016) Molecular pathogenesis of diffuse large B-cell lymphoma. J Clin Exp Hematop 56(2): 71−78 doi: 10.3960/jslrt.56.71
    Dowal L, Provitera P, Scarlata S (2006) Stable association between G alpha(q) and phospholipase C beta 1 in living cells. J Biol Chem 281(33): 23999−24014 doi: 10.1074/jbc.M512330200
    Gadepalli R, Kotla S, Heckle MR, Verma SK, Singh NK, Rao GN (2013) Novel role for p21-activated kinase 2 in thrombin-induced monocyte migration. J Biol Chem 288(43): 30815−30831 doi: 10.1074/jbc.M113.463414
    Gan X, Wang C, Patel M, Kreutz B, Zhou M, Kozasa T, Wu D (2013) Different Raf protein kinases mediate different signaling pathways to stimulate E3 ligase RFFL gene expression in cell migration regulation. J Biol Chem 288(47): 33978−33984 doi: 10.1074/jbc.M113.477406
    Gan X, Wang J, Wang C, Sommer E, Kozasa T, Srinivasula S, Alessi D, Offermanns S, Simon MI, Wu D (2012) PRR5L degradation promotes mTORC2-mediated PKC-delta phosphorylation and cell migration downstream of Galpha12. Nat Cell Biol 14(7): 686−696 doi: 10.1038/ncb2507
    Grzelinski M, Pinkenburg O, Buch T, Gold M, Stohr S, Kalwa H, Gudermann T, Aigner A (2010) Critical role of G(alpha)12 and G(alpha)13 for human small cell lung cancer cell proliferation in vitro and tumor growth in vivo. Clin Cancer Res 16(5): 1402−1415 doi: 10.1158/1078-0432.CCR-09-1873
    Guo RF, Riedemann NC, Bernacki KD, Sarma VJ, Laudes IJ, Reuben JS, Younkin EM, Neff TA, Paulauskis JD, Zetoune FS, Ward PA (2003) Neutrophil C5a receptor and the outcome in a rat model of sepsis. FASEB J 17(13): 1889−1891
    Guo RF, Ward PA (2005) Role of C5a in inflammatory responses. Annu Rev Immunol 23: 821−852 doi: 10.1146/annurev.immunol.23.021704.115835
    Ha JH, Jayaraman M, Yan M, Dhanasekaran P, Isidoro C, Song YS, Dhanasekaran DN (2021) Identification of GNA12-driven gene signatures and key signaling networks in ovarian cancer. Oncol Lett 22(4): 719. https://doi.org/10.3892/ol.2021.12980
    Hashimoto S, Mikami S, Sugino H, Yoshikawa A, Hashimoto A, Onodera Y, Furukawa S, Handa H, Oikawa T, Okada Y, Oya M, Sabe H (2016) Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer. Nat Commun 7: 10656. https://doi.org/10.1038/ncomms10656
    Jain U, Woodruff TM, Stadnyk AW (2013) The C5a receptor antagonist PMX205 ameliorates experimentally induced colitis associated with increased IL-4 and IL-10. Br J Pharmacol 168(2): 488−501 doi: 10.1111/j.1476-5381.2012.02183.x
    Jiang H, Kuang Y, Wu Y, Smrcka A, Simon MI, Wu D (1996) Pertussis toxin-sensitive activation of phospholipase C by the C5a and fMet-Leu-Phe receptors. J Biol Chem 271(23): 13430−13434 doi: 10.1074/jbc.271.23.13430
    Johswich K, Martin M, Bleich A, Kracht M, Dittrich-Breiholz O, Gessner JE, Suerbaum S, Wende E, Rheinheimer C, Klos A (2009) Role of the C5a receptor (C5aR) in acute and chronic dextran sulfate-induced models of inflammatory bowel disease. Inflamm Bowel Dis 15(12): 1812−1823 doi: 10.1002/ibd.21012
    Joshi S, Wels C, Beham-Schmid C, Fukunaga-Kalabis M, Holmen SL, Otte M, Herlyn M, Waldhoer M, Schaider H (2015) Galpha13 mediates human cytomegalovirus-encoded chemokine receptor US28-induced cell death in melanoma. Int J Cancer 137(6): 1503−1508 doi: 10.1002/ijc.29506
    Kaser A, Zeissig S, Blumberg RS (2010) Inflammatory bowel disease. Annu Rev Immunol 28: 573−621 doi: 10.1146/annurev-immunol-030409-101225
    Klinker JF, Wenzel-Seifert K, Seifert R (1996) G-protein-coupled receptors in HL-60 human leukemia cells. Gen Pharmacol 27(1): 33−54 doi: 10.1016/0306-3623(95)00107-7
    Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D (2000) Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractant-mediated signal transduction. Science 287(5455): 1046−1049 doi: 10.1126/science.287.5455.1046
    Liu Z, Lee J, Krummey S, Lu W, Cai H, Lenardo MJ (2011) The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol 12(11): 1063−1070 doi: 10.1038/ni.2113
    Marder SR, Chenoweth DE, Goldstein IM, Perez HD (1985) Chemotactic responses of human peripheral blood monocytes to the complement-derived peptides C5a and C5a des Arg. J Immunol 134(5): 3325−3331 doi: 10.4049/jimmunol.134.5.3325
    McCole DF (2014) IBD candidate genes and intestinal barrier regulation. Inflamm Bowel Dis 20(10): 1829−1849 doi: 10.1097/MIB.0000000000000090
    Moers A, Nieswandt B, Massberg S, Wettschureck N, Gruner S, Konrad I, Schulte V, Aktas B, Gratacap MP, Simon MI, Gawaz M, Offermanns S (2003) G13 is an essential mediator of platelet activation in hemostasis and thrombosis. Nat Med 9(11): 1418−1422 doi: 10.1038/nm943
    Monsinjon T, Gasque P, Chan P, Ischenko A, Brady JJ, Fontaine MC (2003) Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells. FASEB J 17(9): 1003−1014 doi: 10.1096/fj.02-0737com
    Monteleone G, Fina D, Caruso R, Pallone F (2006) New mediators of immunity and inflammation in inflammatory bowel disease. Curr Opin Gastroenterol 22(4): 361−364 doi: 10.1097/01.mog.0000231808.10773.8e
    Mu G, Ding Q, Li H, Zhang L, Zhang L, He K, Wu L, Deng Y, Yang D, Wu L, Xu M, Zhou J, Yu H (2018) Gastrin stimulates pancreatic cancer cell directional migration by activating the Galpha12/13-RhoA-ROCK signaling pathway. Exp Mol Med 50(5): 1−14
    Platt AM, Bain CC, Bordon Y, Sester DP, Mowat AM (2010) An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation. J Immunol 184(12): 6843−6854 doi: 10.4049/jimmunol.0903987
    Rebecchi MJ, Pentyala SN (2000) Structure, function, and control of phosphoinositide-specific phospholipase C. Physiol Rev 80(4): 1291−1335 doi: 10.1152/physrev.2000.80.4.1291
    Sabath E, Negoro H, Beaudry S, Paniagua M, Angelow S, Shah J, Grammatikakis N, Yu AS, Denker BM (2008) Galpha12 regulates protein interactions within the MDCK cell tight junction and inhibits tight-junction assembly. J Cell Sci 121(Pt 6): 814-824
    Strathmann MP, Simon MI (1991) G alpha 12 and G alpha 13 subunits define a fourth class of G protein alpha subunits. Proc Natl Acad Sci USA 88(13): 5582−5586 doi: 10.1073/pnas.88.13.5582
    Suvorova ES, Gripentrog JM, Miettinen HM (2005) Different endocytosis pathways of the C5a receptor and the N-formyl peptide receptor. Traffic 6(2): 100−115 doi: 10.1111/j.1600-0854.2004.00256.x
    Szigethy E, McLafferty L, Goyal A (2010) Inflammatory bowel disease. Child Adolesc Psychiatr Clin N Am 19(2): 301−318,ix doi: 10.1016/j.chc.2010.01.007
    van den Bos E, Ambrosy B, Horsthemke M, Walbaum S, Bachg AC, Wettschureck N, Innamorati G, Wilkie TM, Hanley PJ (2020) Knockout mouse models reveal the contributions of G protein subunits to complement C5a receptor-mediated chemotaxis. J Biol Chem 295(22): 7726−7742 doi: 10.1074/jbc.RA119.011984
    Van Epps DE, Simpson SJ, Johnson R (1993) Relationship of C5a receptor modulation to the functional responsiveness of human polymorphonuclear leukocytes to C5a. J Immunol 150(1): 246−252 doi: 10.4049/jimmunol.150.1.246
    Ward Y, Lake R, Yin JJ, Heger CD, Raffeld M, Goldsmith PK, Merino M, Kelly K (2011) LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells. Cancer Res 71(23): 7301−7311 doi: 10.1158/0008-5472.CAN-11-2381
    Yanamadala V, Negoro H, Gunaratnam L, Kong T, Denker BM (2007) Galpha12 stimulates apoptosis in epithelial cells through JNK1-mediated Bcl-2 degradation and up-regulation of IkappaBalpha. J Biol Chem 282(33): 24352−24363 doi: 10.1074/jbc.M702804200
    Zhang Q, Pan Y, Zeng B, Zheng X, Wang H, Shen X, Li H, Jiang Q, Zhao J, Meng ZX, Li P, Chen Z, Wei H, Liu Z (2019) Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells. Cell Res 29(7): 516−532 doi: 10.1038/s41422-019-0190-3
    Zhang T, Garstka MA, Li K (2017) The controversial C5a receptor C5aR2: its role in health and disease. J Immunol Res 2017: 8193932. https://doi.org/10.1155/2017/8193932
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