cAMP-dependent Protein Kinase Signalling Pathways This series of slides are freely available for individual use for educational purposes. For any other uses, please contact Dr. Steven Pelech by phone at 1-866-KINEXUS or by e-mail at spelech@kinexus.ca. Produced by Dr. Steven Pelech Kinexus Bioinformatics Corporation Copyright 2010

PKA Signalling cAMP PDK1 T197 PKA 1. Epidermal growth factor (EGF) binds to the extracellular domain of the EGF receptor monomer.

PKA Signalling cAMP PDK1 PKA T197 S23 T288 T260 S364 S21 S36 T18 AurA BRSK2 CSK GRK1 GRK7 MST3 S43 S259 T108 1. Epidermal growth factor (EGF) binds to the extracellular domain of the EGF receptor monomer. S153 S696 S621 S21 S9 CaMKK1 PCTAIRE1 Ret Raf1 GSK3a GSK3b S815 smMLCK

PKA Signalling cAMP PDK1 PKA T197 S23 T288 T260 S364 S21 S36 T18 AurA BRSK2 CSK GRK1 GRK7 MST3 S43 S259 T108 1. Epidermal growth factor (EGF) binds to the extracellular domain of the EGF receptor monomer. S153 S696 S621 S21 S9 CaMKK1 PCTAIRE1 Ret Raf1 GSK3a GSK3b S815 smMLCK T260 T38 T260 T75 S44 S39 PPP1R14A PPP1R1A HePTP PTPN12

cAMP S106 PDK1 S943 T309 S1177 PDE5A Na,K-ATPase a1 GLPD1 eNOS S529 PKA T197 S133 S44 ANPa R 5-LO CREB ATF2 S23 T288 T260 S364 S21 S36 T18 AurA BRSK2 CSK GRK1 GRK7 MST3 S43 S259 T108 1. Epidermal growth factor (EGF) binds to the extracellular domain of the EGF receptor monomer. S153 S696 S621 S21 S9 CaMKK1 PCTAIRE1 Ret Raf1 GSK3a GSK3b S815 smMLCK S83 S214 T260 T38 T260 T75 S44 S39 PI3KR1 PTPN12 PIP5K1B PPP1R14A PPP1R1A HePTP PTPN12

PKA Signalling www.phosphoNET.ca Substrate Substrate Full Name ProteinType Substrate Phospho- Effect of Kinase All Kinases Phosphatase Short Name Swissprot site Phosphorylation Affecting Affecting Affecting 5-LO Aarachidonate 5- Enzyme P09917 S523 Phosphorylation inhibits PKACa PKACa lipoxygenase 5-LO activity ANP-alpha R Atrial natriuretic peptide Guanylyl cyclase; P16066 S529 Phosphorylation PKACa PKACa A- type receptor Protein kinaseProtein- activates guanylate serine kinase cyclase activity. (receptor, RGC group, RGC family ATF2 Activating transcription Transcription protein P15336 S44 Phosphorylation PKACa VRK1 (human factor-2 activates transcriptional vaccinia virus- activity. related kinase 1), PKACa Aurora-A Aurora-family kinase 1 Protein-serine kinase, O14965 T288 Phosphorylation PKACa PAK1, PKACa, PPP1CA Other group, AUR increases AurA family phosphotransferase activity. BRSK2 BR serine/threonine- Protein-serine kinase, Q8IWQ3 T260 Phosphorylation PKACa PKACa protein kinase 2 CAMK group, CAMKL increases family, BRSK phosphotransferase subfamily activity. CaMKK1 Calcium/calmodulin- Protein-serine kinase, Q8N5S9 T108 Phosphorylation inhibits PKACa PKACa, CaMK1 dependent protein kinase Other group, CAMKK phosphotransferase 1 alpha family, Meta subfamily activity. CREB cAMP response element- Transcription protein P16220 S133 Phosphorylation PKACa PKACa, RSK1, binding protein increases transcriptional RSK2, RSK3, 1. Epidermal growth factor (EGF) binds to the extracellular domain of the EGF receptor monomer. activity. MSK1, CaMK1- alpha, CaMK2- alpha, CaMK4 Csk C-terminus of Src kinase Protein-tyrosine P41240 S364 Phosphorylation PKACa PKACa kinase, TK group, Csk increases family phosphotransferase activity via SH3 domain of Csk. eNOS Endothelial nitric oxide Synthetase P29474 S1177 Phosphorylation PKACa PKACa, synthetase increases enzymatic PKBa/Akt1, activity of eNOS. PKG1 ER81 ETS ETS translocation variant Transcription protein P50549 S191 Phosphorylation PKACa RSK1, PKACa transcription 1 activates transcriptional factor activity. ER81 ETS ETS translocation variant Transcription protein P50549 S216 Phosphorylation PKACa RSK1, PKACa transcription 1 activates transcriptional factor activity.

PKA Signalling www.phosphoNET.ca Substrate Substrate Full Name ProteinType Substrate Phospho- Effect of Kinase All Kinases Phosphatase Short Name Swissprot site Phosphorylation Affecting Affecting Affecting GPLD1 Phosphatidylinositol- Phospholipase P80108 T309 Phosphorylation inhibits PKACa PKACa glycan-specific enzymatic activity. phospholipase D GRK1 G protein-coupled Protein-serine kinase, Q15835 S21 Phosphorylation inhibits PKACa PKACa receptor kinase 1 AGC group, GRK phosphotransferase family, GRK subfamily activity. GRK7 G protein-coupled Protein-serine kinase, Q8WTQ7 S23 Phosphorylation inhibits PKACa PKACa receptor kinase 7 AGC group, GRK phosphotransferase family, GRK subfamily activity. GRK7 G protein-coupled Protein-serine kinase, Q8WTQ7 S36 Phosphorylation inhibits PKACa PKACa receptor kinase 7 AGC group, GRK phosphotransferase family, GRK subfamily activity. GSK3-alpha Glycogen synthase kinase-3 alpha Protein-serine kinase, P49840 S21 Phosphorylation inhibits PKACa PKBa/Akt1, CMGC group, GSK phosphotransferase PKACa, PKCa, family activity. PKCb, PKCd, PKCg, PKCh, PKCz, RSK2 GSK3-beta Glycogen synthase kinase-3 beta Protein-serine kinase, P49841 S9 Phosphorylation inhibits PKACa PKBa/Akt1, PPP1CA CMGC group, GSK phosphotransferase KHS1, p70S6K, family activity. PKACa, PKCa, PKCb, PKCd, PKCg, PKCh, 1. Epidermal growth factor (EGF) binds to the extracellular domain of the EGF receptor monomer. PKCz, RSK1, RSK2 HePTP Hematopoietic protein- Protein-tyrosine P35236 S44 Phosphorylation inhibits PKACa PKACa PPP1CA tyrosine phosphatase phosphatase interaction with ERK2. hnRNP-A1 RNA binding protein P09651 S199 Phosphorylation inhibits PKACa CK2-A1, PKACa, hnRNP A1 activity. PKBa/Akt1 MST3 Mammalian STE20-like Protein-serine kinase, Q9Y6E0 T18 Phosphorylation PKACa PKACa protein kinase 3 STE group, STE20 increases family, YSK subfamily phosphotransferase activity. Na,K-ATPase Enzyme, hydrolase P05023 S943 Phosphorylation inhibits PKACa PKACa alpha(1) its enzyme activity. subunit PCTAIRE1 PCTAIRE-motif protein Protein-serine kinase, Q00536 S153 Phosphorylation inhibits PKACa PKACa kinase 1 CMGC group, CDK phosphotransferase family, TAIRE activity. subfamily

PKA Signalling www.phosphoNET.ca Substrate Substrate Full Name ProteinType Substrate Phospho- Effect of Kinase All Kinases Phosphatase Short Name Swissprot site Phosphorylation Affecting Affecting Affecting PDE5A cGMP phosphodiesterase Phosphodiesterase O76074 S106 Phosphorylation PKACa PKACa, PKG1 PPP1CA 5 increases phosphodiesterase activity. PIK3R1 Phosphatidylinositol 3- Regulator, inositol P27986 S83 Phosphorylation PKACa PKACa kinase regulatory alpha phosphate metabolism increases enzymatic subunit activity and interaction with ER-alpha, H-Ras-1 and PKAR2B. PIP5K1B Phosphatidylinositol-4- Kinase, lipid, inositol O14986 S214 Phosphorylation inhibits PKACa PKACa PPP1CA phosphate 5-kinase, type phosphate metabolism phosphotransferase I, beta activity. PKACalpha cAMP-dependent protein Protein-serine kinase, P17612 T197 Phosphorylation PKACa PDK1, PKACa kinase alpha catalytic AGC group, PKA increases subunit family phosphotransferase activity. PPP1R14A Protein phosphatase 1, Protein-serine Q96A00 T38 Phosphorylation inhibits PKACa ILK, PKACa, PPP2CA regulatory (inhibitor) phosphatase inhibitor phosphotransferase PKCa, PKCd, subunit 14A activity. PKCd, PKCe, PKCz, PKD1, ROCK2, PAK, PKN, CaMK2 PPP1R1A Protein phosphatase Protein phosphatase Q13522 T75 Phosphorylation induces PKACa PKACa, PKCA inhibitor 1 inhibitor protein activation of the 1. Epidermal growth factor (EGF) binds to the extracellular domain of the EGF receptor monomer. inhibitory activity of this protein towards PPP1CA. PTPN12 Protein-tyrosine Protein-tyrosine Q05209 S39 Phosphorylation inhibits PKACa PKACa, PKCa phosphatase, non- phosphatase phosphotransferase receptor type 12 activity. Raf1 Raf proto-oncogene Protein-serine kinase, P04049 S259 Phosphorylation inhibits PKACa PKACa PPP2CB serine/threonine-protein TKL group, Raf family phosphotransferase kinase activity, reduces H-Ras- 1 and PPP2CB binding, and induces binding of 14-3-3-beta and zeta. It appears to necessary for PKC-alpha activation of Raf1.

PKA Signalling www.phosphoNET.ca Substrate Substrate Full Name ProteinType Substrate Phospho- Effect of Kinase All Kinases Phosphatase Short Name Swissprot site Phosphorylation Affecting Affecting Affecting Raf1 Raf proto-oncogene Protein-serine kinase, P04049 S621 Phosphorylation PKACa PKACa, Raf1 serine/threonine-protein TKL group, Raf family increases kinase phosphotransferase activity and induces interaction with 14-3-3- zeta. Raf1 Raf proto-oncogene Protein-serine kinase, P04049 S43 Phosphorylation inhibits PKACa PKCa, PKACa serine/threonine-protein TKL group, Raf family phosphotransferase kinase activity, inhibits interaction with H-Ras-1 and induces binding of 14-3-3-beta. Ret Proto-oncogene ret Protein-tyrosine kinase P07949 S696 Phosphorylation PKACa PKACa receptor-tyrosine kinase (receptor), TK group, increases for GDNF Ret family phosphotransferase activity. Phosphorylation promotes lamellipodia formation of neuronal cells. smMLCK Myosin light chain kinase, Protein-serine kinase, Q15746 S815 Phosphorylation inhibits PKACa CaMK2, PKACa, smooth muscle and non- CAMK group, MLCK the calmodulin- smMLCK muscle isozymes family dependent activity due to a decrease in the 1. Epidermal growth factor (EGF) binds to the extracellular domain of the EGF receptor monomer. affinity for calmodulin

cAMP PKA - Set 1 Set 2 Set 3 PDK1 PKA PKA AurA Ret BRSK2 Raf1 CaMKK1 O15530 PKA P17612 T197 T197 Set 2 Set 3 PKA P17612 T288 AurA O14965 S696 Ret P07949 T260 S621 BRSK2 Q8IWQ3 Raf1 P04049 T108 S43 S259 S364 S153 CaMKK1 Q8N5S9 1. Epidermal growth factor (EGF) binds to the extracellular domain of the EGF receptor monomer. Raf1 P04049 S21 T18 S23 S21 S9 CSK P41240 S36 PCTAIRE1 Q00536 GRK1 Q15835 MST3 Q9Y6E0 GRK7 Q8WTQ7 GSK3b P49841 GSK3a P49840

cAMP PKA - Set 2 Set 1 Set 3 PDK1 PKA PKA PPP1R1A smMLCK HePTP O15530 PKA P17612 T197 T197 Set 1 Set 3 PKA P17612 S815 T75 PPP1R1A Q13522 smMLCK Q15746 S44 T38 HePTP P35236 PPP1R14A Q96A00 S39 S214 S106 S83 1. Epidermal growth factor (EGF) binds to the extracellular domain of the EGF receptor monomer. PTPN12 Q05209 PIP5K1B O14986 S523 S943 S529 T309 S1177 PDE5A O76074 PI3KR1 P27986 5-LO P09917 Na,K-ATPase a1 P05023 ANPa R P16066 GLPD1 P80108 eNOS P29474

cAMP PKA - Set 3 Set 1 Set 2 PDK1 PKA PKA hnRNP-A1 ATF2 CREB ER81 ETS O15530 PKA P17612 T197 T197 Set 1 Set 2 PKA P17612 S199 hnRNP-A1 P09651 S44 1. Epidermal growth factor (EGF) binds to the extracellular domain of the EGF receptor monomer. S133 S191 S216 ATF2 P15336 CREB P16220 ER81 ETS P50549