Protein Kinase A (PKA) - A Potential Target for Therapeutic Intervention of Dysfunctional Immune Cells

Abstract

In several cases of immunodeficiency and autoimmunity, the dysfunctional immune system is associated with either hypo- or hyperactive T and B cells. In autoimmune conditions such as systemic lupus erythematosus (SLE) and immunodeficiencies such as acquired immunodeficiency syndrome (AIDS), it has been demonstrated that the regulatory effect of the signaling pathway of cyclic 3', 5' adenosine monophosphate (cAMP) and cAMP-dependent protein kinase (PKA) is abrogated. PKA is well-known as a key regulator of immune responses in that it inhibits both early and late phases of antigen induced T and B cell activation. Here we will discuss a potential useful strategy for therapeutic interventions of dysfunctional T cells associated with SLE and HIV by modulation of the cAMP-PKA pathway. Therefore, we will describe the components and architecture of the cAMP-PKA signaling pathway in T cells in order to point out one or several steps which potentially may serve as targets for therapeutic intervention.

Modulation of KV1.3 channels by protein kinase A I in T lymphocytes is mediated by the disc large 1-tyrosine kinase Lck complex

“…PKA is composed of two catalytic (C) and two regulatory (R) subunits, and it exists in two isoforms defined by their respective R subunits (RI␣/RI␤ and RII␣/ RII␤; Ref. 39). We used siRNAs designed against the regulatory subunit I-␣ (RI␣) of PKAI (siPKAI) and the regulatory subunit II-␣ (RII␣) of PKAII (siPKAII) to knock down PKAI and PKAII, respectively (Fig.…”

“…PKA is a holoenzyme composed of two catalytic (C) and two regulatory (R) subunits, and it exists in two isoforms defined by their respective R subunits (RI␣/RI␤ and RII␣/ RII␤; Ref. 39). Each R subunit has two cooperative cAMP binding sites.…”

Dichotomous role of protein kinase A type I (PKAI) in the tumor microenvironment: A potential target for ‘two-in-one’ cancer chemoimmunotherapeutics

“…The disrupted RI/PKAI-RII/PKAII balance is considered a key event in variety of pathological disorders, including cancer [13][14][15]. As will be described in more detail below, the increased RI/PKAI levels have long been implicated in neoplastic transformation and tumor growth [16].…”

Protein Kinase A-Dependent Phosphorylation of Serine 119 in the Proto-Oncogenic Serine/Arginine-Rich Splicing Factor 1 Modulates Its Activity as a Splicing Enhancer Protein

“…28 Specificity in this signal transduction pathway is obtained by compartmentalization by A-kinase anchoring proteins (AKAPs) and by expression of multiple forms of the R and C subunits, which are expressed in a tissuespecific manner and harbor different physiochemical properties. 29,30 Several C subunit-binding proteins have also been identified during recent years. 29,[31][32][33][34] PKA is activated upon binding of 4 molecules of cAMP to the R dimer, releasing the C subunits to phosphorylate relevant substrates on serine and threonine residues in its vicinity.…”

“…29,30 Several C subunit-binding proteins have also been identified during recent years. 29,[31][32][33][34] PKA is activated upon binding of 4 molecules of cAMP to the R dimer, releasing the C subunits to phosphorylate relevant substrates on serine and threonine residues in its vicinity. 35 However, a proportion of the C subunit translocates to the nucleus after activation, where it is involved in the regulation of transcription and splicing.…”