Protein Kinase C-θ Isoenzyme Selective Stimulation of the Transcription Factor Complex AP-1 in T Lymphocytes

Abstract

Molecular cloning and biochemical studies identified protein kinase C (PKC) enzymes as members of a distinct family of serine/threonine protein kinases, playing critical roles in the regulation of cellular differentiation and proliferation of diverse cell types (reviewed in reference 36). In an attempt to find PKC isoforms that are involved in growth control and/or activation of T lymphocytes, we have identified PKC-(5), whose human gene locus was recently mapped to chromosome 10p15 (15). PKC-is characterized by a unique tissue distribution, i.e., in skeletal muscle, lymphoid organs, and hematopoietic cell lines, particularly T cells (4,5,10,34,39,53), and by isoenzyme-specific activation requirements and substrate preferences in vitro (4). PKC-undergoes cytosol-to-membrane translocation in T cells stimulated with phorbol esters (4), implying that this isoform is likely to be involved in T-cell activation pathways. The unique expression and functional properties of PKC-suggest that it may play a specialized role in T-cell signaling pathways.T-cell activation results in the expression of interleukin-2 (IL-2), an autocrine growth factor that is a critical stimulus for the growth and differentiation of B and T lymphocytes. Pharmacological and biochemical studies indicate that activation of two major signaling pathways, one of which can be triggered by phorbol esters (such as phorbol 12-myristate 13-acetate [PMA]) and the other of which can be triggered by Ca 2ϩ ionophores, is required for induction of IL-2 (reviewed in reference 51). A substantial amount of work over the past several years has shown the requirement of cooperative interactions of several transcription factors, including AP-1, NF-B, NF-AT, and NF-IL2A (Oct-1), with the minimal inducible promoter/enhancer region of the IL-2 gene (11). Several lines of evidence point to AP-1 as a critical transcription factor for IL-2 regulation. AP-1 is a dimer of different members of the Fos (c-Fos, FosB, Fra-1, Fra-2, and FosB2) and Jun (c-Jun, JunB, and JunD) family of proteins (1). AP-1 thereby interacts with the IL-2 regulatory region directly (25,26,33,47) and also indirectly as a component of NF-AT and NF-IL2 (37, 50). AP-1 activity is regulated by de novo synthesis of Jun and Fos proteins, as well as by posttranslational modifications such as phosphorylation and dephosphorylation (1,8,9,30,43,48). Two potential AP-1-binding sites have been identified in the mouse and human IL-2 enhancer region at Ϫ150 bp (proximal AP-1) and Ϫ180 bp (distal AP-1). These elements show sequence similarity to the consensus AP-1 enhancer sequence and have been studied by deletional, mutational, and gel shift analyses (14,18,25,40). Most of these data support an important role for AP-1 in IL-2 transcription, especially as a result of the interaction with the proximal enhancer site (25).PKC has been implicated in the activation of AP-1 in T lymphocytes, as demonstrated by studies involving PKC-specific pharmacological inhibitors (24, 28) or PKC down-regulation by chronic phorbol este...

Menin represses JunD transcriptional activity in protein kinase Cθ-mediated Nur77 expression

“…It has been shown that PKC , a predominant isoform of PKC in T cells, activates AP-1 and NF-κB transcription factors in IL-2 production (Baier-Bitterlich et al, 1996;Sun et al, 2000). However, there are neither NF-κB response element nor exact AP-1 element, instead, four AP-1-like elements (TGCGTCA;NAP1,NAP2,NAP3,NAP4, in the murine Nur77 promoter.…”

Protein Kinase C-θ Phosphorylation of Moesin in the Actin-binding Sequence

“…The chromosomal location of the human PKC-gene was mapped to the short arm of chromosome 10 (10p15), a region that is frequently deleted or subject to translocations in T-cell leukemia, lymphoma, and T-cell immunodeficiency (59). In T-lymphocytes, PKC-in conjunction with 14-3-3 may be a constituent of the signaling cascade leading to T-cell activation by activating the AP-1 transcriptional complex (60). Recent evidence clearly shows that antigen stimulation results in the translocation of PKC-, along with talin, to the site of contact between T-cells and antigen-presenting cells, whereas in unstimulated cells PKCis found in a punctate distribution (46).…”

Resistance to Experimental Autoimmune Encephalomyelitis and Impaired IL-17 Production in Protein Kinase Cθ-Deficient Mice

“…The T lymphocyte-restricted serine/threonine protein kinase protein kinase C (PKC ) 2 is unique among other PKC members because it colocalizes with the TCR in the T cell immunological synapse (2)(3)(4). In cultured cell lines, PKC -mediated signal transduction has been shown to result in activation of the transcription factors, AP-1 and NF-B, in response to TCR/ CD28 costimulation, ultimately culminating in the induction of expression of genes that are essential for the proliferation and function of activated T cells (5)(6)(7)(8). The physiological functions of PKC for TCR signaling were subsequently demonstrated by two independent studies with PKC -deficient mice (9,10).…”

“…Peripheral T cells of PKC Ϫ/Ϫ mice show reduced proliferation and IL-2 production and significant impairment in AP-1 and NF-B (9, 10) as well as NFAT (10) activation in response to TCR/CD28 stimulation. Although numerous studies have implicated the I B␣ kinase IKK complex in linking PKC to NF-B activation (5)(6)(7)(8), the pathway responsible for coupling PKC to AP-1 appears to be JNK independent (9). Recently, a study has identified the stress-related STE20/ SPS1-like, proline alanine-rich kinase, SPAK, as a substrate and target of PKC in a TCR/CD28-induced signaling pathway leading to selective activation of AP-1, but not NF-B (11).…”