The Novel PKCθfrom Benchtop to Clinic

Abstract

The protein kinases C (PKCs) are a family of serine/threonine kinases involved in regulating multiple essential cellular processes such as survival, proliferation, and differentiation. Of particular interest is the novel, calcium-independent PKCθ which plays a central role in immune responses. PKCθ shares structural similarities with other PKC family members, mainly consisting of an N-terminal regulatory domain and a C-terminal catalytic domain tethered by a hinge region. This isozyme, however, is unique in that it translocates to the immunological synapse between a T cell and an antigen-presenting cell (APC) upon T cell receptor-peptide MHC recognition. Thereafter, PKCθ interacts physically and functionally with downstream effectors to mediate T cell activation and differentiation, subsequently leading to inflammation. PKCθ-specific perturbations have been identified in several diseases, most notably autoimmune disorders, and hence the modulation of its activity presents an attractive therapeutic intervention. To that end, many inhibitors of PKCs and PKCθ have been developed and tested in preclinical and clinical studies. And although selectivity remains a challenge, results are promising for the future development of effective PKCθ inhibitors that would greatly advance the treatment of several T-cell mediated diseases.

Genetic insights into the mechanisms of Fgf signaling

“…Pkcs are a family of serine threonine kinases organized into three categories based on mechanisms of activation (Hage-Sleiman et al 2015). Conventional (c) Pkcs (α, β, and γ) are activated by DAG, Ca 2+ , and phorbol esters, while novel (n) Pkcs (δ, ε, η, and θ) are activated by DAG and phorbol esters but not Ca 2+ .…”

“…Conventional (c) Pkcs (α, β, and γ) are activated by DAG, Ca 2+ , and phorbol esters, while novel (n) Pkcs (δ, ε, η, and θ) are activated by DAG and phorbol esters but not Ca 2+ . Atypical (a) Pkcs (ζ, ι, and μ) are activated by protein-protein interactions rather than secondary messengers (Hage-Sleiman et al 2015). Fgfrs engage Pkc through Plcγ (Fig.…”

Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders

“…Other PKC-related-kinases (PRKs) include PRK1–3 and are also considered a fourth group of the PKC family (Mellor and Parker, 1998). PRKs are similar in structure to PKCs except for the C1 region, but do not bind Ca 2+ , DAG, or phorbol esters, and have homology region 1 (HR1) motifs responsible for RhoA binding (Hage-Sleiman et al, 2015). …”

“…As a result of phosphorylation of the activation loop, a negative charge is introduced that properly aligns residues to form a competent catalytic domain and facilitate the subsequent autophosphorylation of 2 sites in the C-terminus, one at the ‘turn motif’, so named because it corresponds to a phosphorylation site in PKA localized at the apex of a turn, and the other at the more C-terminal hydrophobic motif (Behn-Krappa and Newton, 1999). The hydrophobic motif is an important and direct mediator of PKC stability, functioning as a docking-site for PDK-1 through its repeated negatively charged aspartate sequence called PDK-1 interacting fragment (Balendran et al, 2000; Newton, 2003); an interaction that allows PDK-1 to access the activation loop (Hage-Sleiman et al, 2015). …”

“…In cPKCs, both the turn motif and the hydrophobic motif are autophosphorylated, whereas in nPKCs autophosphorylation occurs only in the turn motif, and phosphorylation in the hydrophobic motif is carried out by other kinases (Hage-Sleiman et al, 2015). For PKCδ, autophosphorylation of its turn motif contributes to its relative stability and solubility.…”