Kinase Subfamily PKCh
Kinase Classification: Group AGC: Family PKC: Subfamily PKCh
PKCh (PKCη or PKC-eta)is one of two 'novel' PKC subfamilies
Evolution
PKCh members are found in metazoa and choanoflagellates, with two mammalian members, PKC epsilon (PKCe/ε) and eta (PKCh/η). The Drosophila homolog is Pkc98E and the worm is kin-13/pkc-1
Domain Structure
Like the PKCd subfamily, PKCh have an N-terminal variant C2 domain followed by two C1 domains (the reverse orientation to what is seen in PKCa), and a kinase domain
Functions
Both human forms have tissue-selective RNA expression with PKCe expressed most highly in kidney, lung, and brain and spermatids, while PKCh is more broadly expressed with peaks in in T cells, erythroid and endothelial cells, endocrine, and digestive tissues (ProteinAtlas.org).
Model organism homologs are less well studied. Drosophila Pkc98E interacts with Notch non-canonical signaling and may phosphorylate cactus/IkB, regulates odorant responses by phosphorylation the odorant co-receptor ORCO, and mediates response to ethanol through NPY signaling.
C. elegans pkc-1 regulates neuropeptide release and recycling of dense core vesicles [1], and human PKCe [2] is required for the activity-dependent potentiation (exocytosis) of DCVs, possibly through it's phosphorylation of the substrate MARCKS. At the rat neuromuscular junction, PKCe phosphorylation of MARKCs is correlated with acetylcholine release, and may be activated by TrkB signaling [3]
NFkB signaling
PKCe is implicated in NFkB signaling in multiple species. Human PKCe is mono-ubiquitinated by RINCK1 ubiquitin ligase in response to EGFR activation. This causes association with the ubiquitin-binding domain of nemo, recruiting the IKK complex to the cell membrane, where PKCe phosphorylates and activates IKKb at Ser177[4]. miR-31 targets PKCe and blocks NFkB signaling in breast cancer cells [4], and in a mouse cardiac ischemia model [5]. In Drosophila embryos, Pkc98E is linked to high Notch expression and phosphorylation of the NFkB regulatory subunit, IkB/cactus [6]
Alcohol Response
Ethanol response in Drosophila involves different PKCs in different neurons: Pkc98E is implicated in signaling through NPY/NPF neurons, while the PKCa homolog, Pkc53E is involved with serotonin-modulates neurons [7]. In mammals, PKCe has multiple associations with alcohol responses [8]
References
- Sieburth D, Madison JM, and Kaplan JM. PKC-1 regulates secretion of neuropeptides. Nat Neurosci. 2007 Jan;10(1):49-57. DOI:10.1038/nn1810 |
- Park YS, Hur EM, Choi BH, Kwak E, Jun DJ, Park SJ, and Kim KT. Involvement of protein kinase C-epsilon in activity-dependent potentiation of large dense-core vesicle exocytosis in chromaffin cells. J Neurosci. 2006 Aug 30;26(35):8999-9005. DOI:10.1523/JNEUROSCI.2828-06.2006 |
- Obis T, Besalduch N, Hurtado E, Nadal L, Santafe MM, Garcia N, Tomàs M, Priego M, Lanuza MA, and Tomàs J. The novel protein kinase C epsilon isoform at the adult neuromuscular synapse: location, regulation by synaptic activity-dependent muscle contraction through TrkB signaling and coupling to ACh release. Mol Brain. 2015 Feb 10;8:8. DOI:10.1186/s13041-015-0098-x |
- Körner C, Keklikoglou I, Bender C, Wörner A, Münstermann E, and Wiemann S. MicroRNA-31 sensitizes human breast cells to apoptosis by direct targeting of protein kinase C epsilon (PKCepsilon). J Biol Chem. 2013 Mar 22;288(12):8750-8761. DOI:10.1074/jbc.M112.414128 |
- Wang Y, Men M, Yang W, Zheng H, and Xue S. MiR-31 Downregulation Protects Against Cardiac Ischemia/Reperfusion Injury by Targeting Protein Kinase C Epsilon (PKCε) Directly. Cell Physiol Biochem. 2015;36(1):179-90. DOI:10.1159/000374062 |
- Tremmel DM, Resad S, Little CJ, and Wesley CS. Notch and PKC are involved in formation of the lateral region of the dorso-ventral axis in Drosophila embryos. PLoS One. 2013;8(7):e67789. DOI:10.1371/journal.pone.0067789 |
- Chen J, Zhang Y, and Shen P. Protein kinase C deficiency-induced alcohol insensitivity and underlying cellular targets in Drosophila. Neuroscience. 2010 Mar 10;166(1):34-9. DOI:10.1016/j.neuroscience.2009.12.009 |
- Pakri Mohamed RM, Mokhtar MH, Yap E, Hanim A, Abdul Wahab N, Jaffar FHF, and Kumar J. Ethanol-Induced Changes in PKCε: From Cell to Behavior. Front Neurosci. 2018;12:244. DOI:10.3389/fnins.2018.00244 |
- Yang W, Xia Y, Cao Y, Zheng Y, Bu W, Zhang L, You MJ, Koh MY, Cote G, Aldape K, Li Y, Verma IM, Chiao PJ, and Lu Z. EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis. Mol Cell. 2012 Dec 14;48(5):771-84. DOI:10.1016/j.molcel.2012.09.028 |
