Pathway Map Details

Immune response_Function of MEF2 in T lymphocytes

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Object list (links open in MetaCore):, Calcineurin A (catalytic), 14-3-3, HDAC4, PLC-gamma 1, TCR alpha/beta, NUR77, MEF2, HDAC1, MAP3K2 (MEKK2), MEK6(MAP2K6), ERK5 (MAPK7), PtdIns(4,5)P2, Ca('2+) = Ca('2+), NF-AT1(NFATC2), HDAC5, CD3, CABIN1, PCAF, MAP2K5 (MEK5), Ca('2+) endoplasmic reticulum lumen, CaMKK, Ca('2+) = Ca('2+), IL-2, Sin3A, Lck, HDAC2, HDAC7, IP3, Ca('2+) cytosol, p38beta (MAPK11), HDAC9, NCOA2 (GRIP1/TIF2), p38alpha (MAPK14), MEF2C, Ca('2+) extracellular region, MEF2A, CARM1, IP3 receptor, CaMK I, Calmodulin, ZAP70, Calcineurin A (beta), p300, PKC, CaMK IV, MAP3K3, c-Jun, MEF2D, LAT


Function of MEF2 in T lymphocytes.

Myocyte enhancer factors 2 ( MEF2 ) is a family of muscle-enriched transcription factors that have an essential role in myogenesis. In addition, MEF2 is also expressed at high levels in neurons and lymphocytes, where it serves as a regulator of neuronal and immune cell differentiation and function [1], [2].

MEF2 is necessary for the transcriptional activation of Interleukin 2 ( IL-2 ) (and possible other cytokines) during peripheral T cell activation [3]. It plays a crucial role in T-lymphocyte apoptosis by regulating expression of Nuclear receptor subfamily 4, group A, member 1 ( NUR77 ) [4], [5].

To date, four MEF2 proteins have been identified: MEF2A, MEF2B, MEF2C, and MEF2D, which are expressed in distinct, but overlapping patterns during embryogenesis, and in adult tissues. MEF2 proteins form homo- and heterodimers that constitutively bind to response elements [2].

In T lymphocytes, MEF2 activity is subjected to complex levels of regulation. MEF2 associates with a variety of regulating proteins: K(lysine) acetyltransferase 2B ( PCAF ), Binding protein p300 ( p300 ), Nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 ( NF-AT1(NFATC2) ), Nuclear receptor coactivator 2 ( NCOA2 (GRIP1/TIF2) ), Myogenic differentiation 1 ( MYOD ), 14-3-3, Mitogen-activated protein kinase 7 ( ERK5 (MAPK7) ), Calcineurin binding protein 1 ( CABIN1 ), Histone deacetylases 4, 5 7 and 9 ( HDAC4, HDAC5, HDAC7, HDAC9 ) and is regulated by MAP kinase cascades and calcium signaling.

Calcium regulates MEF2 activity by three different mechanisms: via Calcium/calmodulin-dependent protein kinases ( CaMKK ), NF-AT1(NFATC2) and CABIN1.

Association of MEF2 with HDAC4, HDAC5, HDAC7 and HDAC9 results in deacetylation of nucleosomal histones surrounding MEF2 DNA-binding sites, with subsequent suppression of MEF2 -dependent genes. Calcium/calmodulin-dependent protein kinases I and IV ( CaMK I and CaMK IV ) phosphorylate HDACs, creating docking sites for a chaperone protein 14-3-3. Upon binding of 14-3-3, HDACs are released from MEF2 and transported (except HDAC9 ) to the cytoplasm via a C-terminal nuclear export sequence. Once released from associated repressors, MEF2 is bound by the p300 co-activator [2].

Calcium-bound Calmodulin 2 ( Calmodulin ) also associates with and activates Protein phosphatase 3 (formerly 2B), catalytic subunits ( Calcineurin A (catalytic) ). Calcineurin A (catalytic) dephosphorylates NF-AT1(NFATC2) leading to its translocation into the nucleus. In the nucleus NF-AT1(NFATC2) directly associates with MEF2A and MEF2D and recruits p300 co-activator to MEF2 target genes [2]. Upon T cell activation, a subpopulation of Calcineurin A (catalytic) translocates into the nucleus to maintain the transcriptional activity of NF-AT1(NFATC2) and other factors [6].

Additionally, MEF2 can associate with CABIN1, which recruits Histone deacetylases 1 and 2 ( HDAC1, HDAC2 ) via SIN3 homolog A, transcription regulator ( Sin3A ) co-repressor, resulting in deacetylation of local histones and repression of MEF2 target gene transcription [4].

In response to increased intracellular Ca('2+), Calmodulin is activated and associated with the MEF2 -binding region of CABIN1, releasing MEF2 so that it can associate with NF-AT1(NFATC2) - p300 complexes and activate target gene expression.

CABIN1 also associates with and represses Calcineurin A (catalytic), and thus inhibits MEF2 activity by inhibiting an upstream activator of MEF2 -dependent transcription.

T cell receptor alpha/ beta ( TCR alpha/beta ) signaling pathway is known to be down-regulated in the course of T cell activation [6] CABIN1 was hypothesized to function in down-modulating TCR alpha/beta signaling via Calcineurin A (catalytic) activity [4], [5].

Protein kinase C ( PKC ) activation leads to hyperphosphorylation of CABIN1, which appears to be required for its high-affinity interaction with Calcineurin A (catalytic) [6].

p300 and PCAF are histone acetyltransferases (HATs). They acetylate histone tails, relaxing chromatin surrounding MEF2 target sites, with subsequent stimulation of transcription of MEF2 target gene [2].

MAPKs couple MEF2 to multiple signaling pathways for cell growth and differentiation.

It was shown that Mitogen activated protein kinases 14 and 11 ( p38alpha (MAPK14), p38beta (MAPK11) ) phosphorylate and activate MEF2A and MEF2C and ERK5 (MAPK7) is capable of phosphorylating and activating MEF2A, MEF2C and MEF2D [7], [8].

ERK5 (MAPK7) can also function as a transcriptional co-activator by recruiting basal transcriptional machinery [2]. ERK5 (MAPK7), itself is phosphorylated and activated by Mitogen-activated protein kinase kinase kinase2 and 3 ( MAP3K2 (MEKK2) and MAP2K3 ) [9].

In response to p38alpha (MAPK14), p38beta (MAPK11 ) and ERK5(MAPK7) MEF2 activates the transcription factor Jun oncogene ( c-Jun ), which participates in regulation of proliferation [10], [11], [2].


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