Chapter Seven - A most versatile kinase: The catalytic subunit of PKA in T-cell biology
Section snippets
A brief introduction to PKA biology
PKA, which is formally designated as cAMP-dependent protein kinase (EC 2.7.11.11), is a highly promiscuous serine/threonine kinase with over 250 identified substrates (Soberg and Skalhegg, 2018). In the absence of activating stimuli, PKA typically forms a tetrameric holoenzyme consisting of two regulatory subunits (PKAr) that bind and inactivate two catalytic subunits (PKAc). Classical PKA activation results from binding of an extracellular signal, such as prostaglandin E2 (PGE2), to its
PKA as a regulator of NF-κB activity
One of the more enigmatic PKA substrates is the p65 subunit of the transcription factor NF-κB (Zhong et al., 1997). p65 is one of five NF-κB family members, which hold critical roles in the regulation of multiple biological processes including cell survival, differentiation, proliferation, and, in particular, the immune response. The members of the NF-κB family exist as different combinations of homo- and heterodimers, which regulate distinct but overlapping gene sets. The most prevalent of
The role of cAMP and PKA in T cells
Increasing the intracellular concentration of cAMP, and thereby activating PKA, for extended periods of time is generally associated with immunosuppressive effects. In fact, several microbial species, including such important pathogens as Mycobacterium tuberculosis, Bacillus anthracis and Plasmodium falciparum, have evolved mechanisms to increase cAMP levels in host cells to blunt the immune response (McDonough and Rodriguez, 2011). While immunosuppression by cAMP is better understood in innate
The translational relevance of PKA
Only few diseases have been linked to PKA defects, presumably due to the embryonic lethality associated with PKA dysfunction. Important examples include point mutations in PRKACA, which are found frequently in adrenocortical tumors that produce excessive levels of cortisol and thus cause Cushing's syndrome (Beuschlein et al., 2014; Cao et al., 2014; Cheung et al., 2015); a large-scale deletion on chromosome 19 that creates an oncogenic fusion protein of DnaJ B1 and PKAc isoform Cα (DNAJB1-PRKACA
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