Details of the Target

General Information of Target

Target ID LDTP02909
Target Name cAMP-dependent protein kinase catalytic subunit alpha (PRKACA)
Gene Name PRKACA
Gene ID 5566
Synonyms
PKACA; cAMP-dependent protein kinase catalytic subunit alpha; PKA C-alpha; EC 2.7.11.11
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MGNAAAAKKGSEQESVKEFLAKAKEDFLKKWESPAQNTAHLDQFERIKTLGTGSFGRVML
VKHKETGNHYAMKILDKQKVVKLKQIEHTLNEKRILQAVNFPFLVKLEFSFKDNSNLYMV
MEYVPGGEMFSHLRRIGRFSEPHARFYAAQIVLTFEYLHSLDLIYRDLKPENLLIDQQGY
IQVTDFGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALGVLIYEMAAGYPPFF
ADQPIQIYEKIVSGKVRFPSHFSSDLKDLLRNLLQVDLTKRFGNLKNGVNDIKNHKWFAT
TDWIAIYQRKVEAPFIPKFKGPGDTSNFDDYEEEEIRVSINEKCGKEFSEF
Target Type
Patented-recorded
Target Bioclass
Enzyme
Family
Protein kinase superfamily, AGC Ser/Thr protein kinase family, cAMP subfamily
Subcellular location
Cytoplasm
Function
Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, SOX9 and VASP. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in chondrogenesis by mediating phosphorylation of SOX9. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Required for phosphorylation of GLI transcription factors which inhibits them and prevents transcriptional activation of Hedgehog signaling pathway target genes. GLI transcription factor phosphorylation is inhibited by interaction of PRKACA with SMO which sequesters PRKACA at the cell membrane. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis most probably through the regulation of OFD1 in ciliogenesis. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G and AICDA. Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock. Acts as a negative regulator of mTORC1 by mediating phosphorylation of RPTOR.; [Isoform 2]: Phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation.
TTD ID
T20669
Uniprot ID
P17612
DrugMap ID
TTV0HK8
Ensemble ID
ENST00000308677.9
HGNC ID
HGNC:9380
ChEMBL ID
CHEMBL4101

Target Site Mutations in Different Cell Lines

Cell line Mutation details Probe for labeling this protein in this cell
LS180 SNV: p.N284D .
MELJUSO SNV: p.N341T .
MFE319 Insertion: p.V227GfsTer5
SNV: p.V192A		 .
MOLT4 SNV: p.A305S .

Probe(s) Labeling This Target

ABPP Probe
Click To Hide/Show 13 Probe Related to This Target
Probe name Structure Binding Site(Ratio) Interaction ID Ref
C-Sul
 Probe Info  		14.39  LDD0066  [1]
STPyne
 Probe Info  		K22(0.76); K24(3.79); K293(9.47); K310(2.50)  LDD0277  [2]
ONAyne
 Probe Info  		K293(2.33)  LDD0275  [2]
OPA-S-S-alkyne
 Probe Info  		K48(1.56)  LDD3494  [3]
Probe 1
 Probe Info  		Y331(13.93)  LDD3495  [4]
BTD
 Probe Info  		C344(0.43)  LDD2091  [5]
Acrolein
 Probe Info  		N.A.  LDD0223  [6]
ATP probe
 Probe Info  		K267(0.00); K320(0.00)  LDD0199  [7]
4-Iodoacetamidophenylacetylene
 Probe Info  		N.A.  LDD0038  [8]
IA-alkyne
 Probe Info  		C344(0.00); C200(0.00)  LDD0036  [8]
Lodoacetamide azide
 Probe Info  		C344(0.00); C200(0.00)  LDD0037  [8]
NHS
 Probe Info  		N.A.  LDD0010  [9]
NAIA_5
 Probe Info  		N.A.  LDD2223  [10]
PAL-AfBPP Probe
Click To Hide/Show 6 Probe Related to This Target
Probe name Structure Binding Site(Ratio) Interaction ID Ref
FFF probe13
 Probe Info  		20.00  LDD0475  [11]
FFF probe14
 Probe Info  		10.40  LDD0477  [11]
FFF probe3
 Probe Info  		20.00  LDD0464  [11]
VE-P
 Probe Info  		N.A.  LDD0396  [12]
DA-2
 Probe Info  		N.A.  LDD0071  [13]
STS-1
 Probe Info  		N.A.  LDD0069  [14]

Competitor(s) Related to This Target

Competitor ID Name Cell line Binding Site(Ratio) Interaction ID Ref
 LDCM0502  1-(Cyanoacetyl)piperidine MDA-MB-231 C344(0.70)  LDD2095  [5]
 LDCM0537  2-Cyano-N,N-dimethylacetamide MDA-MB-231 C344(1.00)  LDD2130  [5]
 LDCM0539  3-(4-Isopropylpiperazin-1-yl)-3-oxopropanenitrile MDA-MB-231 C344(0.55)  LDD2132  [5]
 LDCM0538  4-(Cyanoacetyl)morpholine MDA-MB-231 C344(1.50)  LDD2131  [5]
 LDCM0545  Acetamide MDA-MB-231 C344(0.47)  LDD2138  [5]
 LDCM0498  BS-3668 MDA-MB-231 C344(0.43)  LDD2091  [5]
 LDCM0528  N-(4-bromophenyl)-2-cyano-N-phenylacetamide MDA-MB-231 C344(0.43)  LDD2121  [5]
 LDCM0109  NEM HeLa N.A.  LDD0223  [6]
 LDCM0527  Nucleophilic fragment 26b MDA-MB-231 C344(0.79)  LDD2120  [5]
 LDCM0529  Nucleophilic fragment 27b MDA-MB-231 C344(0.41)  LDD2122  [5]
 LDCM0535  Nucleophilic fragment 30b MDA-MB-231 C344(0.71)  LDD2128  [5]
 LDCM0546  Nucleophilic fragment 40 MDA-MB-231 C344(0.62)  LDD2140  [5]
 LDCM0549  Nucleophilic fragment 43 MDA-MB-231 C344(1.23)  LDD2143  [5]
 LDCM0553  Nucleophilic fragment 6b MDA-MB-231 C344(5.18)  LDD2147  [5]
 LDCM0556  Nucleophilic fragment 8a MDA-MB-231 C344(0.45)  LDD2150  [5]
 LDCM0557  Nucleophilic fragment 8b MDA-MB-231 C344(0.55)  LDD2151  [5]

The Interaction Atlas With This Target

The Protein(s) Related To This Target

Enzyme
Click To Hide/Show 20 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Adenylate kinase 2, mitochondrial (AK2) Adenylate kinase family P54819
Cystathionine beta-synthase (CBS) Cysteine synthase/cystathionine beta-synthase family P35520
DNA dC->dU-editing enzyme APOBEC-3G (APOBEC3G) Cytidine and deoxycytidylate deaminase family Q9HC16
Single-stranded DNA cytosine deaminase (AICDA) Cytidine and deoxycytidylate deaminase family Q9GZX7
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) Glyceraldehyde-3-phosphate dehydrogenase family P04406
Heat shock protein HSP 90-alpha (HSP90AA1) Heat shock protein 90 family P07900
Isocitrate dehydrogenase [NADP] cytoplasmic (IDH1) Isocitrate and isopropylmalate dehydrogenases family O75874
Polyunsaturated fatty acid 5-lipoxygenase (ALOX5) Lipoxygenase family P09917
Dihydropyrimidinase-related protein 4 (DPYSL4) Hydantoinase/dihydropyrimidinase family O14531
Phospholipid phosphatase 1 (PLPP1) PA-phosphatase related phosphoesterase family O14494
Ubiquitin carboxyl-terminal hydrolase 25 (USP25) Peptidase C19 family Q9UHP3
Kell blood group glycoprotein (KEL) Peptidase M13 family P23276
Proprotein convertase subtilisin/kexin type 7 (PCSK7) Peptidase S8 family Q16549
Purine nucleoside phosphorylase (PNP) PNP/MTAP phosphorylase family P00491
26S proteasome non-ATPase regulatory subunit 2 (PSMD2) Proteasome subunit S2 family Q13200
RAC-alpha serine/threonine-protein kinase (AKT1) AGC Ser/Thr protein kinase family P31749
Glycogen synthase kinase-3 beta (GSK3B) CMGC Ser/Thr protein kinase family P49841
Leucine-rich repeat serine/threonine-protein kinase 2 (LRRK2) TKL Ser/Thr protein kinase family Q5S007
Ataxin-3 (ATXN3) . P54252
E3 ubiquitin-protein ligase CHIP (STUB1) . Q9UNE7
Transporter and channel
Click To Hide/Show 5 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Amyloid-beta precursor protein (APP) APP family P05067
Huntingtin (HTT) Huntingtin family P42858
Integrin alpha-V (ITGAV) Integrin alpha chain family P06756
Protein S100-B (S100B) S-100 family P04271
Cadherin-1 (CDH1) . P12830
Transcription factor
Click To Hide/Show 3 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Mothers against decapentaplegic homolog 3 (SMAD3) Dwarfin/SMAD family P84022
Protein C-ets-2 (ETS2) ETS family P15036
Transcription factor Sp6 (SP6) Sp1 C2H2-type zinc-finger protein family Q3SY56
Other
Click To Hide/Show 12 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Ataxin-1 (ATXN1) ATXN1 family P54253
cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A) CAMP-dependent kinase regulatory chain family P10644
cAMP-dependent protein kinase type I-beta regulatory subunit (PRKAR1B) CAMP-dependent kinase regulatory chain family P31321
cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B) CAMP-dependent kinase regulatory chain family P31323
Large ribosomal subunit protein eL43 (RPL37A) Eukaryotic ribosomal protein eL43 family P61513
Protein VCF1 (VCF1) FAM104 family Q969W3
Pleiotrophin (PTN) Pleiotrophin family P21246
T-complex protein 1 subunit zeta (CCT6A) TCP-1 chaperonin family P40227
A-kinase-interacting protein 1 (AKIP1) . Q9NQ31
Arginine vasopressin-induced protein 1 (AVPI1) . Q5T686
BAG family molecular chaperone regulator 2 (BAG2) . O95816
TRAF3-interacting JNK-activating modulator (TRAF3IP3) . Q9Y228

The Drug(s) Related To This Target

Approved
Click To Hide/Show 1 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Fostamatinib Small molecular drug DB12010
Investigative
Click To Hide/Show 70 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Isis 102450 Antisense drug D08FVO
Isis 102454 Antisense drug D0L0IR
Isis 102458 Antisense drug D0V2VB
Isis 102462 Antisense drug D00YID
Isis 102466 Antisense drug D0M4NN
Isis 102478 Antisense drug D0S7SN
Isis 102482 Antisense drug D0Z2QO
Isis 102486 Antisense drug D0K7PJ
Isis 102490 Antisense drug D03RKU
Isis 102558 Antisense drug D0A5FV
Isis 102563 Antisense drug D02XQB
Isis 102584 Antisense drug D04OUT
Isis 102599 Antisense drug D0CE4H
Isis 102604 Antisense drug D00ODF
Isis 102609 Antisense drug D0P0SY
Isis 102614 Antisense drug D06NSN
Isis 102619 Antisense drug D00WZE
Isis 102624 Antisense drug D0T3GH
Isis 102629 Antisense drug D06JUQ
Isis 102633 Antisense drug D00ERI
Isis 102660 Antisense drug D0U3ML
Isis 102664 Antisense drug D04GPC
Isis 102668 Antisense drug D0KL5K
Isis 102676 Antisense drug D0D4BR
(2s)-1-(1h-indol-3-yl)-3-{[5-(3-methyl-1h-indazol-5-yl)Pyridin-3-yl]Oxy}Propan-2-amine Small molecular drug DB08073
(S)-2-methyl-1-[(4-methyl-5-isoquinoline)Sulfonyl]-homopiperazine Small molecular drug DB07876
4-[(3,5-diamino-1h-pyrazol-4-yl)Diazenyl]Phenol Small molecular drug D0A5RM
5-(2-methylpiperazine-1-sulfonyl)Isoquinoline Small molecular drug DB07996
A-674563 Small molecular drug DB08568
Balanol Small molecular drug DB04098
Dexfosfoserine Small molecular drug DB04522
Ellagic Acid Small molecular drug DB08846
Fasudil Small molecular drug DB08162
H-89 Small molecular drug D09FFE
Hydroxyfasudil Small molecular drug DB04707
Myristic Acid Small molecular drug DB08231
N-[2-(Methylamino)Ethyl]-5-isoquinolinesulfonamide Small molecular drug DB07997
Nm-pp1 Small molecular drug D0GT8N
Phosphonothreonine Small molecular drug DB02482
Ro-4396686 Small molecular drug D09XIL
Ss-(2-hydroxyethyl)Thiocysteine Small molecular drug DB04530
Y-27632 Small molecular drug DB08756
(1s)-1-(1h-indol-3-ylmethyl)-2-(2-pyridin-4-yl-[17]Naphtyridin-5-yloxy)-ehylamine . DB07204
(1s)-2-(1h-indol-3-yl)-1-[({5-[(E)-2-pyridin-4-ylvinyl]Pyridin-3-yl}Oxy)Methyl]Ethylamine . DB07107
(2r)-2-(4-chlorophenyl)-2-phenylethanamine . DB07860
(2r)-2-(4-chlorophenyl)-2-[4-(1h-pyrazol-4-yl)Phenyl]Ethanamine . DB07857
(2s)-1-(3h-indol-3-yl)-3-{[5-(6-isoquinolinyl)-3-pyridinyl]Oxy}-2-propanamine . DB06959
(2s)-1-(6h-indol-3-yl)-3-{[5-(7h-pyrazolo[34-c]Pyridin-5-yl)Pyridin-3-yl]Oxy}Propan-2-amine . DB07124
(2s)-1-{[5-(1h-indazol-5-yl)-3-pyridinyl]Oxy}-3-(7ah-indol-3-yl)-2-propanamine . DB06977
(2s)-2-(4-chlorophenyl)-2-[4-(1h-pyrazol-4-yl)Phenyl]Ethanamine . DB07858
(4r2s)-5'-(4-(4-chlorobenzyloxy)Pyrrolidin-2-ylmethanesulfonyl)Isoquinoline . DB07583
(S)-1-phenyl-1-[4-(9h-purin-6-yl)Phenyl]Methanamine . DB07855
1-[4-(4-chlorobenzyl)-1-(7h-pyrrolo[23-d]Pyrimidin-4-yl)Piperidin-4-yl]Methanamine . DB08149
1-[4-(4-chlorophenyl)-1-(7h-pyrrolo[23-d]Pyrimidin-4-yl)Piperidin-4-yl]Methanamine . DB08148
2-[4-(3-methyl-1h-pyrazol-4-yl)Phenyl]Ethanamine . DB08070
3-(1h-indol-3-yl)-4-{1-[2-(1-methylpyrrolidin-2-yl)Ethyl]-1h-indol-3-yl}-1h-pyrrole-25-dione . DB07458
3-pyridin-4-yl-1h-indazole . DB08113
3-pyridin-4-yl-24-dihydro-indeno[12-.C.] Pyrazole . DB08569
3-[(3-sec-butyl-4-hydroxybenzoyl)Amino]Azepan-4-yl 4-(2-hydroxy-5-methoxybenzoyl)Benzoate . DB02155
35-diiodotyrosine . DB03374
4-(4-chlorobenzyl)-1-(7h-pyrrolo[23-d]Pyrimidin-4-yl)Piperidin-4-aminium . DB08150
4-(4-chlorophenyl)-4-[4-(1h-pyrazol-4-yl)Phenyl]Piperidine . DB07859
5-benzyl-13-thiazol-2-amine . DB08114
6-{4-[4-(4-chlorophenyl)Piperidin-4-yl]Phenyl}-9h-purine . DB07856
Balanol Analog 1 . DB02611
Balanol Analog 2 . DB01940
Isoquinoline-5-sulfonic Acid (2-(2-(4-chlorobenzyloxy)Ethylamino)Ethyl)Amide . DB07947
N-methyl-1-[4-(9h-purin-6-yl)Phenyl]Methanamine . DB07854
N-[(1s)-2-amino-1-(24-dichlorobenzyl)Ethyl]-5-[2-(Methylamino)Pyrimidin-4-yl]Thiophene-2-carboxamide . DB07235
Pentanal . DB01919
Patented
Click To Hide/Show 3 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Agggwzcoulseer-pyuwxlgesa-n Small molecular drug D0B6VY
Vfedeoubybldkn-aafjcebusa-n Small molecular drug D00QNV
Xhpnyyouzwownt-pyuwxlgesa-n Small molecular drug D06GXM
Discontinued
Click To Hide/Show 1 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Balanol Small molecular drug D0R2TM

References

1 Low-Toxicity Sulfonium-Based Probes for Cysteine-Specific Profiling in Live Cells. Anal Chem. 2022 Mar 15;94(10):4366-4372. doi: 10.1021/acs.analchem.1c05129. Epub 2022 Mar 4.
2 A Paal-Knorr agent for chemoproteomic profiling of targets of isoketals in cells. Chem Sci. 2021 Oct 15;12(43):14557-14563. doi: 10.1039/d1sc02230j. eCollection 2021 Nov 10.
Mass spectrometry data entry: PXD028270
3 A chemical proteomics approach for global mapping of functional lysines on cell surface of living cell. Nat Commun. 2024 Apr 8;15(1):2997. doi: 10.1038/s41467-024-47033-w.
Mass spectrometry data entry: PXD042888
4 An Azo Coupling-Based Chemoproteomic Approach to Systematically Profile the Tyrosine Reactivity in the Human Proteome. Anal Chem. 2021 Jul 27;93(29):10334-10342. doi: 10.1021/acs.analchem.1c01935. Epub 2021 Jul 12.
5 Nucleophilic covalent ligand discovery for the cysteine redoxome. Nat Chem Biol. 2023 Nov;19(11):1309-1319. doi: 10.1038/s41589-023-01330-5. Epub 2023 May 29.
Mass spectrometry data entry: PXD039908 , PXD029761
6 ACR-Based Probe for the Quantitative Profiling of Histidine Reactivity in the Human Proteome. J Am Chem Soc. 2023 Mar 8;145(9):5252-5260. doi: 10.1021/jacs.2c12653. Epub 2023 Feb 27.
7 Targeted Proteomic Approaches for Proteome-Wide Characterizations of the AMP-Binding Capacities of Kinases. J Proteome Res. 2022 Aug 5;21(8):2063-2070. doi: 10.1021/acs.jproteome.2c00225. Epub 2022 Jul 12.
8 Enhancing Cysteine Chemoproteomic Coverage through Systematic Assessment of Click Chemistry Product Fragmentation. Anal Chem. 2022 Mar 8;94(9):3800-3810. doi: 10.1021/acs.analchem.1c04402. Epub 2022 Feb 23.
Mass spectrometry data entry: PXD028853
9 A modification-centric assessment tool for the performance of chemoproteomic probes. Nat Chem Biol. 2022 Aug;18(8):904-912. doi: 10.1038/s41589-022-01074-8. Epub 2022 Jul 21.
Mass spectrometry data entry: PXD027758 , PXD027755 , PXD027760 , PXD027762 , PXD027756 , PXD027591 , PXD007149 , PXD030064 , PXD032392 , PXD027789 , PXD027767 , PXD027764
10 N-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable cysteines and oxidized thiols by chemoproteomics. Nat Commun. 2023 Jun 15;14(1):3564. doi: 10.1038/s41467-023-39268-w.
Mass spectrometry data entry: PXD041264
11 Ligand and Target Discovery by Fragment-Based Screening in Human Cells. Cell. 2017 Jan 26;168(3):527-541.e29. doi: 10.1016/j.cell.2016.12.029. Epub 2017 Jan 19.
12 Pharmacological Targeting of Vacuolar H(+)-ATPase via Subunit V1G Combats Multidrug-Resistant Cancer. Cell Chem Biol. 2020 Nov 19;27(11):1359-1370.e8. doi: 10.1016/j.chembiol.2020.06.011. Epub 2020 Jul 9.
13 Cell-based proteome profiling of potential dasatinib targets by use of affinity-based probes. J Am Chem Soc. 2012 Feb 15;134(6):3001-14. doi: 10.1021/ja208518u. Epub 2012 Feb 1.
14 Proteome profiling reveals potential cellular targets of staurosporine using a clickable cell-permeable probe. Chem Commun (Camb). 2011 Oct 28;47(40):11306-8. doi: 10.1039/c1cc14824a. Epub 2011 Sep 16.