29 These proteins, which belong to the bZIP group Protein Tyrosine Kinase inhibitor of DNA-binding proteins, have leucine zippers through which they associate

to form a variety of homo- and hetero-dimers that bind to common AP-1 sites (TRE-TGAC/GTCA) or (CRE-TGACTCA) in DNA.30 Both ATF (ATF2, ATF3, B-ATF, JDP1, JDP2) and Maf (c-MAF, MafA, MafB, Nr1) are also considered members of this family based on their dimerization potential with Fos or Jun.29 Jun-proteins, but not Fos-proteins, are known to undergo homo-dimerization.31 Hetero-dimerization of Fos with Jun is crucial for nuclear-cytoplasmic shuttling.32 Monomeric Fos and Jun shuttle actively but hetero-dimerization of both proteins inhibits their cytoplasmic shuttling. Surprisingly, this retro-transport inhibition is not caused by the binding of the AP-1 complex to DNA.32 Levels of Fos and Jun proteins in T cells are either low or absent and are generally induced on signalling.33,34 Activity of AP-1 is regulated by mitogen-activated protein kinases (MAPK).35,36 Extra-cellular signal-regulated kinase (ERK) activation causes c-Fos induction, which results in increased synthesis of c-Fos and translocation to the nucleus. VX 809 In the nucleus it combines with pre-existing Jun proteins to form AP-1 dimers that are more stable than those formed by Jun proteins alone.30 It has been shown that ERK-1 is associated with the

synapse after TCR stimulation and prevents docking of Src homology-2 (SH2) domain-containing phosphatase -1 (SHP-1) phospha-tase.37–39 Transcription of c-Fos is regulated by ternary complex factors (Elk-1, SAP-1 and SAP-2) of which Elk-1 is phosphorylated by ERK.30,40 The c-Jun is expressed at low levels in unstimulated cells and its promoter is constitutively occupied by Jun-activating transcription factor 2 (ATF2) dimer.41,42 Phosphorylation of c-Jun by Jun N-terminal kinases (JNKs) and of ATF2 by JNKs or p38MAPK stimulates their ability to activate transcription, thereby leading to c-Jun induction.30 As part of their negative

regulation, AP-1 proteins are degraded in both ubiquitin-dependent and ubiquitin-independent manners.43–45 The GSK-3 can inhibit AP-1 transcriptional activity by producing inhibitory phosphorylation on Jun.12,46 The MAPK are negatively regulated by MAPK phosphatases, which are known to interact with the cytoplasmic tail of CD28 and are regulated by CD28 signalling.47,48 Mice OSBPL9 lacking c-Jun die at mid-gestation, indicating that it is an essential factor required for development.49 Mice lacking c-Fos are growth retarded and develop osteoporosis with a reduced number of B cells.50,51 The function of peripheral T cells (including proliferation and production of cytokines), however, is not impaired in c-Fos knockout mice.52 This lack of impairment could be the result of degeneracy among Fos members. In T cells, AP-1 contributes significantly to the regulation of the IL-2 gene.53 The main transcriptional partners of AP-1 are NFAT proteins.