cAMP-dependent Protein Kinase Signalling Pathways

1. cAMP-dependent Protein Kinase Signalling Pathways Produced by Dr. Steven Pelech Kinexus Bioinformatics Corporation Copyright 2010

2. T197 PKA PDK1 PKA Signalling cAMP

3. Ret CSK S9 S696 S21 S153 S23 S36 S364 S21 S815 S621 S259 S43 T197 T288 T260 T18 T108 smMLCK GSK3b MST3 BRSK2 GRK7 PCTAIRE1 Raf1 GRK1 GSK3a AurA PKA CaMKK1 PDK1 PKA Signalling cAMP

4. CSK Ret PPP1R14A PPP1R1A S696 S815 S39 S44 S9 S153 S21 S23 S364 S21 S621 S259 S36 S43 PTPN12 HePTP T288 T75 T260 T197 T260 T18 T38 T260 T108 Raf1 PDK1 AurA BRSK2 GRK1 MST3 PCTAIRE1 PKA GSK3b CaMKK1 GSK3a smMLCK GRK7 PKA Signalling cAMP

5. Ret CSK PPP1R14A PIP5K1B eNOS ANPa R PPP1R1A GLPD1 5-LO PI3KR1 PDE5A S696 S21 S943 S1177 S39 S44 S214 S529 S44 S9 S106 S815 S23 S83 S43 S259 S621 S133 S523 S21 S153 S364 S36 PTPN12 PTPN12 HePTP T260 T288 T260 T18 T260 T108 T197 T38 T75 T309 smMLCK AurA Raf1 GSK3b GSK3a MST3 BRSK2 PKA GRK7 PDK1 CaMKK1 PCTAIRE1 GRK1 ATF2 CREB Na,K-ATPase a1 cAMP

6. 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, 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.

7. 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, 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

8. 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 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.

9. 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 affinity for calmodulin

10. Ret P07949 CSK P41240 MST3 Q9Y6E0 BRSK2 Q8IWQ3 CaMKK1 Q8N5S9 GRK1 Q15835 GRK7 Q8WTQ7 GSK3b P49841 GSK3a P49840 PCTAIRE1 Q00536 Raf1 P04049 Raf1 P04049 PKA P17612 PDK1 O15530 AurA O14965 PKA P17612 S696 S9 S153 S21 S621 S21 S259 S364 S23 S36 S43 T18 T197 T260 T288 T197 T108 PKA - Set 1 cAMP Set 2 Set 3

11. S943 S106 S529 S1177 S83 S523 S44 S39 S815 S214 T197 T75 T309 T38 T197 PKA - Set 2 cAMP PDK1 O15530 PKA P17612 Set 1 Set 3 PKA P17612 PPP1R1A Q13522 smMLCK Q15746 HePTP P35236 PPP1R14A Q96A00 PIP5K1B O14986 PTPN12 Q05209 PI3KR1 P27986 PDE5A O76074 Na,K-ATPase a1 P05023 5-LO P09917 ANPa R P16066 GLPD1 P80108 eNOS P29474

12. S199 S133 S191 S216 S44 T197 T197 PKA - Set 3 cAMP PDK1 O15530 PKA P17612 Set 1 Set 2 PKA P17612 hnRNP-A1 P09651 ATF2 P15336 CREB P16220 ER81 ETS P50549