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C6mb00255b1.Pdf Electronic Supplementary Material (ESI) for Molecular BioSystems. This journal is © The Royal Society of Chemistry 2016 Journal Name ARTICLE Supplementary material Supplementary file 1: Network assembly Note that Λ indicates the logical connection AND → indicates activation and -І indicates inhibition. node node connection and type reference Weight in SQUAD simulation 5,00 angiotensin II → Gq-coupled AT1receptor [1] 10,00 carbachol → Gi-coupled M2 receptor [1] Epac → PKC [2] 10,00 ERK 1/2 dim 2P → p90RSK [1] 0,01 ERK 1/2 dim 2P → p70S6K [1] 0,01 ERK 1/2 dim 2P –І AND: 100,00 AND –І ERK 1/2 dim 3P: 1,00 ERK 1/2 dim 2P Λ Gβγ → ERK 1/2 dim 3P [1] Gβγ → ERK 1/2 dim 3P: 100,00 ERK 1/2 dim 3P → Elk1 [1] 8,00 ERK 1/2 dim 3P → MSK1 [1] 7,00 ERK 1/2 dim 3P → c-Myc [1] 6,00 10,00 Gi-coupled M2 receptor → Ras (GTP bound) [1] Gi-coupled M2 receptor → PKC [3] 10,00 10,00 Gq-coupled AT1receptor → Gβγ [1] 1,00 Gq-coupled AT1receptor → Ras (GTP bound) [1] Gq-coupled AT1receptor → PKC [4] 10,00 Gs-coupled β1-adrenergic 0,10 GRK2 -І receptor [5] Gs-coupled β 1-adrenergic 1,00 receptor → Ras (GTP bound) [6] Gs-coupled β1-adrenergic 10,00 receptor → Gβγ [6] Gs-coupled β1-adrenergic 10,00 receptor → Epac [2] hypertrophic stimulus → angiotensin II [1] 1,00 hypertrophic stimulus → isoproterenol [6] 10,00 Gs-coupled β1-adrenergic 10,00 isoproterenol → receptor [6] MEK 1/2 → ERK 1/2 dim 2P [1] 0,001 non-hypertrophic stimulus → carbachol [1] 10,00 PKC -І RKIP [7] 10,00 PKC → RKIP dim [7] 10,00 Raf1 → MEK 1/2 [1] 1,00 Ras (GTP bound) → Raf1 [1] 10,00 RKIP -І Raf1 [7] 0,01 RKIP dim -І GRK2 [7] 30,00 This journal is © The Royal Society of Chemistry 2012 Molecular Biosystems, 2015, 00, 1-3 | 1 ARTICLE Journal Name Supplementary file 2: SQUAD readouts after a non-hypertrophic/hypertrophic stimulus A) non-hypertrophic stimulus B) hypertrophic stimulus 2 | Molecular Biosystems, 2015, 00, 1-3 This journal is © The Royal Society of Chemistry 2012 Journal Name ARTICLE Supplementary file 3: possible ERK targets1 5500 18224 type Erk- Targets official symbol (NCBI) GSE adjusted P-value GSE adjusted P-value Localisatio n additional informatio n MAPK isoform cell reference TACE ADAM17 cell ERK acts as an intermediate in protein kinase Erk1/2 [8] surface, C-regulated TrkA cleavage. The cytosolic tail of golgi TACE is phosphorylated by Erk at threonine apparat 735. ERK and TACE associate. us GRK 2 ADRBK1 ERK1 phosphorylates GRK2. Inhibition of ERK Erk1 HEK2 [9] activity potentiates GRK2 activity, whereas, 93 conversely, ERK activation inhibits GRK2 cells activity. feedback regulatory loop! ALK ALK vesicle ALK mediates growth and differentiation of - - [10] neurons, ERK is essentially involved p85 ARHGEF7 Erk activates p85 via binding of PAK2 to Erk - PC12 [11] betaPI and as a result of this PAK2 and p85 are cell X building a complex and translocate -> neurite lines growth CREB2 ATF2 3,4*10- nucleus Raf-MEK-Erk pathway induces phosphorylation - fibrobl [12], 2 of ATF2 at Thr71 and Ral-RalGDS-Src-p38 asts [13] pathway at Thr69 -> both required for activation; but: other study shows that Erk- activation is not required for ATF2-activation bromo BAZ1B novel mechanisms of epigenetic regulation of Erk1 - [14] domain MAPK (amongst others Erk1): Phosphorylation adjace of Williams syndrome transcription factor by nt to them induces a switch between two different zinc chromatin remodeling complexes finger domain , 1B BRAF BRAF cytosol BRAF mutations activate the mitogen-activated [15, and protein kinase pathway 16] nucleus Hyalur C1QBP cytopla is an endogenous substrate for MAP kinase, [17] onan sm, suggestion: ERK activation is requirement for binding nucleus translocation to nucleus protein 1 CAD CAD allosteric regulation of CAD is mediated by [18] MAPK and PKA-mediated phosphorylations → cell-cycle dependent regulation of pyrimidine biosynthesis Calnexi CANX 2,17*1 endopl Phosphorylation by CK2 and MAPK enhances [19] n 0-2 asmic calnexin association with ribosomes → reticulu increase in glycoprotein folding m This journal is © The Royal Society of Chemistry 2012 Molecular Biosystems, 2015, 00, 1-3 | 3 ARTICLE Journal Name 5500 18224 type Erk- Targets official symbol (NCBI) GSE adjusted P-value GSE adjusted P-value Localisatio n additional informatio n MAPK isoform cell reference Caspas CASP8 prolonged Erk-activation results in Caspase8 p38 [20, e 8 activation and cell death, p38MAPK can inhibit MAPK 21] Caspase8 function and thereby hinder apoptosis Caspas CASP9 nucleus Erk phosphorylates and inhibits Caspase9 and [22, e 9 and promotes cell survival and tissue homeostasis 23] cytopla sm Caveoli CAV1 “Caveolin-1 and caveolae play a paradoxical ERK [24] n 1 role in regulating VEGF-induced ERK2/1 1/2 activation and in vitro angiogenesis as evidenced by the similar inhibitory effects of down-regulation and overexpression of caveolin-1 and disruption of caveolae” H4 CCDC6 CCDC6-Ret oncogen phosphorylates and Erk 1/2 LAD [25], Genpro activates Erk -> regulation of cell proliferation cell [26] dukt (CCDC6 Ret genproduct is found in lung lines adenocarcinoma and papillary thyreoid carcinoma) Cep55 CEP55 2,02*1 amongst others Erk2 phosphorylates Cep55 Erk2 [27] 0-2 (centrosome protein) → relocate to midbody →function in cytokinesis and mitotic exit Cortact CTTN 1,03*1 cytopla ERK regulates cortactin ubiquitination and [28] in 0-2 sm degradation in lung epithelial cells DCC DCC DCC activates Erk and this contributes to netrin Erk 1/2 [29, signalling in axon growth and guidance 30] Elk1 ELK1 5,09*1 nucleus IN CASCADE, phosphorylated Erk1/2 Erk1/2 [31] 0-3 and translocated to the nucleus and cytopla phosphorylates Elk1 sm Elk 4 ELK4 nucleus Elk4 is phosphorylated by Erk2 (and MAPK8), Erk2 [32, and Elk4 directly links Erk signaling to the 33] cytopla transcriptional events required for thymocyte sm positive selection, Elk4 is direct androgen receptor target in prostate cancer TNF - R f.e. FAS Polyphenols from Korean prostrate spurge [34] Euphorbia supina induce apoptosis through the Fas-associated extrinsic pathway and activation of ERK in human leukemic U937 cells FCGR2 FCGR2B nuclear Erk1/2 binds to FCGR2B and phosphorylates a Erk1/2 [35] B membr serine residue → thr binding of Lyn to FCGR2B ane and is modified → thus might negatively regulate cytopla phosphorylation of ITIM → signal transduction sm is not inhibited anymore FHL2 FHL2 4,63*1 fhl2 serves a repressor function, it inhibits Erk Erk1/2 [36] 0-2 1/2 transcriptional coupling c - fos FOS nucleus Erk phosphorylates c-fos, as an result the [37] transcriptional activity is increased GAB2 GAB2 cytopla Erk-mediated phosphorylation of Gab2 t- [38] 4 | Molecular Biosystems, 2015, 00, 1-3 This journal is © The Royal Society of Chemistry 2012 Journal Name ARTICLE 5500 18224 type Erk- Targets official symbol (NCBI) GSE adjusted P-value GSE adjusted P-value Localisatio n additional informatio n MAPK isoform cell reference sm regulates assosication with SHP2 and lymph decreases STAT5 activation → fine tuning of ocyte proliferative answer of t-lymphocytes to IL-2 s GATA2 GATA2 nucleus Erk possibly phosphorylates GATA2, involved in hemat [39] growth factor responsiveness and proliferation opoiet of hematopoietic progenitor cells ic proge nitor cells GATA4 GATA4 mainly Erk1/2 regulates cardiomyocyte hypertrophic Erk1/2 cardio [40] nucleus growth via GATA4 through direct myoc phosphorylation yte Connex GJA1 hexameric connexin (Cx)-43 hemichannels are Erk1/2 [41] in 43 the essential transducers of the Erk- activating/anti-apoptotic effects of bisphosphonates GRB10 GRB10 nucleus is a direct substrate of Erk1/2, regulates insulin Erk1/2 - [42] and signaling cytopla sm general GTF2I nucleus ERK regulates the activity of TFII-I by direct Erk1 [43, transcri phosphorylation, regulates its activation of the 44] ption c-fos promoter factor IIi hyaluro HMMR RHAMM (an intracellular cytoskeletal protein) Erk1/2 [45] nan- modulates ERK1/2 signal transduction at mediat microtubules, which can act as barriers to ed mESC pluripotency motilit y recept or (RHAM M) heat HSF1 nucleus association of HSF1 with ERK and 14-3-3ϵ Erk2 [46] shock and during heat shock may thus modulate the transcri cytopla amplitude of the response and lead to efficient ption sm termination of HSP expression on resumption factor of growth conditions 1 Hsp90 HSP90 cytosol extracellular Hsp90 serves as an important co- MAPK [47] factor for KSHV-initiated MAPK activation general (proof-of-concept for the potential benefit of targeting csHsp90 for the treatment or prevention of KSHV-associated illnesses) heat HSPB8 9,8*10- nucleus involved in regulation of cell proliferation, Erk1 in vivo [48] shock 3 and apoptosis; HSPB8 is phosphorylated by This journal is © The Royal Society of Chemistry 2012 Molecular Biosystems, 2015, 00, 1-3 | 5 ARTICLE Journal Name 5500 18224 type Erk- Targets official symbol (NCBI) GSE adjusted P-value GSE adjusted P-value Localisatio n additional informatio n MAPK isoform cell reference 22kDa cytopla amongst others Erk1 (at residues Ser(27) and protein sm Thr(87)) 8 IEX1 IER3 IEX1 is a substrate of Erk, they regulate each Erk2 in vivo [49] other, phosphorylated IEX1 is able to inhibit cell death JAK 2 JAK2 the interaction between TFII-I and ERK, which Erk [43] is essential for its activity, can be regulated by general JAK2 through phosphorylation of TFII-I Sam68 KHDRBS1 4,7*10- nucleus Sam68 acts as a convergence point for ERK Erk1/2/ [50] 3 signaling to cell migration; blockade of 5 phospho-Sam68 may provide a new avenue for therapeutic inhibition of metastatic cancers KSR1 KSR1 KSR1 is a scaffold, enhances signaling between MAPK in vivo [51, Raf, MEK and ERK, Erk phosphorylates KSR1 general 52] LIFR LIFR 1,08*1 ERK-induced event was required, in addition to Erk1/2 [53] 0-2 CREB/ATF-1 phosphorylation, for CREB/ATF-1- mediated transcription of C/EBP genes; essential role for adipocyte differentiation hormo LIPE Erk phosphorylates LIPE in fat cells, in muscle fat [54, nsensit via PKC cells, 55] ive muscl Lipase e cells Lyn LYN Interleukin 2 activates polymorph cored, Erk1 neutro [56] neutrophil granulocytes.
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