Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT1MS7X)

• DTT Name: PKC-theta messenger RNA (PRKCQ mRNA)
• Synonyms: Protein kinase C theta type (mRNA); PRKCT (mRNA); NPKC-theta (mRNA)
• Gene Name: PRKCQ
• DTT Type: Literature-reported target; [1]
• BioChemical Class: mRNA target
• UniProt ID: KPCT_HUMAN
• TTD ID: T72295
• EC Number: EC 2.7.11.13
• Sequence:
  MSPFLRIGLSNFDCGSCQSCQGEAVNPYCAVLVKEYVESENGQMYIQKKPTMYPPWDSTF
  DAHINKGRVMQIIVKGKNVDLISETTVELYSLAERCRKNNGKTEIWLELKPQGRMLMNAR
  YFLEMSDTKDMNEFETEGFFALHQRRGAIKQAKVHHVKCHEFTATFFPQPTFCSVCHEFV
  WGLNKQGYQCRQCNAAIHKKCIDKVIAKCTGSAINSRETMFHKERFKIDMPHRFKVYNYK
  SPTFCEHCGTLLWGLARQGLKCDACGMNVHHRCQTKVANLCGINQKLMAEALAMIESTQQ
  ARCLRDTEQIFREGPVEIGLPCSIKNEARPPCLPTPGKREPQGISWESPLDEVDKMCHLP
  EPELNKERPSLQIKLKIEDFILHKMLGKGSFGKVFLAEFKKTNQFFAIKALKKDVVLMDD
  DVECTMVEKRVLSLAWEHPFLTHMFCTFQTKENLFFVMEYLNGGDLMYHIQSCHKFDLSR
  ATFYAAEIILGLQFLHSKGIVYRDLKLDNILLDKDGHIKIADFGMCKENMLGDAKTNTFC
  GTPDYIAPEILLGQKYNHSVDWWSFGVLLYEMLIGQSPFHGQDEEELFHSIRMDNPFYPR
  WLEKEAKDLLVKLFVREPEKRLGVRGDIRQHPLFREINWEELERKEIDPPFRPKVKSPFD
  CSNFDKEFLNEKPRLSFADRALINSMDQNMFRNFSFMNPGMERLIS
• Function: In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates in the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1. Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2.
• KEGG Pathway:
  NF-kappa B signaling pathway (hsa04064)
  Vascular smooth muscle contraction (hsa04270)
  Tight junction (hsa04530)
  T cell receptor signaling pathway (hsa04660)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Adipocytokine signaling pathway (hsa04920)
  Measles (hsa05162)
• Reactome Pathway:
  Effects of PIP2 hydrolysis (R-HSA-114508)
  Inactivation, recovery and regulation of the phototransduction cascade (R-HSA-2514859)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  G alpha (z) signalling events (R-HSA-418597)
  Apoptotic cleavage of cellular proteins (R-HSA-111465)

Molecular Interaction Atlas (MIA) of This DTT

11 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-(1H-indol-5-ylamino)-5-styrylnicotinonitrile	DMAU0SF	Discovery agent	N.A.	Investigative	[2]
4-(1H-indol-5-yloxy)-5-styrylnicotinonitrile	DMH360U	Discovery agent	N.A.	Investigative	[2]
4-(1H-indol-6-ylamino)-5-styrylnicotinonitrile	DMB07TU	Discovery agent	N.A.	Investigative	[2]
4-(3H-indol-4-ylamino)-5-styrylnicotinonitrile	DMM8AY5	Discovery agent	N.A.	Investigative	[2]
8-Octyl-benzolactam-V9	DM4Z15M	Discovery agent	N.A.	Investigative	[3]
ISIS 109351	DM508BS	Discovery agent	N.A.	Investigative	[1]
ISIS 109352	DMWK1XC	Discovery agent	N.A.	Investigative	[1]
ISIS 109353	DM6AJMC	Discovery agent	N.A.	Investigative	[1]
ISIS 109354	DM1REKQ	Discovery agent	N.A.	Investigative	[1]
ISIS 109355	DMFIQGW	Discovery agent	N.A.	Investigative	[1]
PROSTRATIN	DM1HMJ5	Human immunodeficiency virus infection	1C62	Investigative	[4]

References

• [1] US patent application no. 6,190,869, Antisense inhibition of protein kinase C-theta expression.
• [2] First generation 5-vinyl-3-pyridinecarbonitrile PKCtheta inhibitors. Bioorg Med Chem Lett. 2009 Oct 15;19(20):5829-32.
• [3] Design and synthesis of 8-octyl-benzolactam-V9, a selective activator for protein kinase C epsilon and eta. J Med Chem. 2006 May 4;49(9):2681-8.
• [4] A nonpromoting phorbol from the samoan medicinal plant Homalanthus nutans inhibits cell killing by HIV-1. J Med Chem. 1992 May 29;35(11):1978-86.