mitogen activated protein kinases

Mitogen-activated protein kinase 1

Short name=MAP kinase 1
Short name=MAPK 1
EC=2.7.11.24
Alternative name(s):
ERT1
Extracellular signal-regulated kinase 2
Short name=ERK-2
MAP kinase isoform p42
Short name=p42-MAPK
Mitogen-activated protein kinase 2
Short name=MAP kinase 2
Short name=MAPK 2
Gene names
Name: MAPK1
Synonyms: ERK2, PRKM1, PRKM2

Function

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, DCC, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade. Mediates phosphorylation of TPR in respons to EGF stimulation. May play a role in the spindle assembly checkpoint. Phosphorylates PML and promotes its interaction with PIN1, leading to PML degradation. Ref.7 Ref.8 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.21 Ref.22 Ref.23 Ref.26 Ref.27 Ref.28 Ref.29 Ref.30 Ref.31 Ref.34 Ref.40 Ref.43 Ref.44 Ref.55
Acts as a transcriptional repressor. Binds to a [GC]AAA[GC] consensus sequence. Repress the expression of interferon gamma-induced genes. Seems to bind to the promoter of CCL5, DMP1, IFIH1, IFITM1, IRF7, IRF9, LAMP3, OAS1, OAS2, OAS3 and STAT1. Transcriptional activity is independent of kinase activity. Ref.7 Ref.8 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.21 Ref.22 Ref.23 Ref.26 Ref.27 Ref.28 Ref.29 Ref.30 Ref.31 Ref.34 Ref.40 Ref.43 Ref.44 Ref.55
Catalytic activity
ATP + a protein = ADP + a phosphoprotein.
Cofactor
Magnesium By similarity.
Enzyme regulation
Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-185 and Tyr-187 in response to external stimuli like insulin or NGF. Both phosphorylations are required for activity. This phosphorylation causes dramatic conformational changes, which enable full activation and interaction of MAPK1/ERK2 with its substrates. Phosphorylation on Ser-29 by SGK1 results in its activation by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. Dephosphorylated and inactivated by DUSP3, DUSP6 and DUSP9. Inactivated by pyrimidylpyrrole inhibitors. Ref.19 Ref.48
Subunit structure
Binds both upstream activators and downstream substrates in multimolecular complexes. Binds to HIV-1 Nef through its SH3 domain. This interaction inhibits its tyrosine-kinase activity. Interacts with ADAM15, ARHGEF2, ARRB2, DAPK1 (via death domain), HSF4, IER3, IPO7, DUSP6, NISCH, SGK1, and isoform 1 of NEK2. Interacts (phosphorylated form) with CAV2 ('Tyr-19'-phosphorylated form); the interaction, promoted by insulin, leads to nuclear location and MAPK1 activation. Interacts with MORG1, PEA15 and MKNK2 By similarity. MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation By similarity. Interacts with DCC By similarity. The phosphorylated form interacts with PML (isoform PML-4) Ref.9 Ref.13 Ref.19 Ref.20 Ref.24 Ref.29 Ref.33 Ref.34 Ref.36 Ref.37 Ref.39 Ref.40 Ref.46 Ref.48 Ref.55
Subcellular location
Cytoplasm › cytoskeleton › spindle By similarity. Nucleus. Cytoplasm › cytoskeleton › microtubule organizing center › centrosome. Cytoplasm. Note: Associated with the spindle during prometaphase and metaphase By similarity. PEA15-binding and phosphorylated DAPK1 promote its cytoplasmic retention. Phosphorylation at Ser- 246 and Ser-248 as well as autophosphorylation at Thr-190 promote nuclear localization. Ref.24 Ref.29 Ref.39 Ref.48
Domain
The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
Post-translational modification
Phosphorylated upon KIT and FLT3 signaling By similarity. Dually phosphorylated on Thr-185 and Tyr-187, which activates the enzyme. Undergoes regulatory phosphorylation on additional residues such as Ser-246 and Ser-248 in the kinase insert domain (KID) These phosphorylations, which are probably mediated by more than one kinase, are important for binding of MAPK1/ERK2 to importin-7 (IPO7) and its nuclear translocation. In addition, autophosphorylation of Thr-190 was shown to affect the subcellular localization of MAPK1/ERK2 as well. Ligand-activated ALK induces tyrosine phosphorylation. Dephosphorylated by PTPRJ at Tyr-187. Phosphorylation on Ser-29 by SGK1 results in its activation by enhancing its interaction with MAP2K1/MEK1 and MAP2K2/MEK2. DUSP3 and DUSP6 dephosphorylate specifically MAPK1/ERK2 and MAPK3/ERK1 whereas DUSP9 dephosphorylates a broader range of MAPKs. Ref.14 Ref.35 Ref.39 Ref.44 Ref.45 Ref.46 Ref.48 Ref.64
ISGylated By similarity.
Sequence similarities
Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.
Contains 1 protein kinase domain.

Mitogen-activated protein kinase 3

Short name=MAP kinase 3
Short name=MAPK 3
EC=2.7.11.24
Alternative name(s):
ERT2
Extracellular signal-regulated kinase 1
Short name=ERK-1
Insulin-stimulated MAP2 kinase
MAP kinase isoform p44
Short name=p44-MAPK
Microtubule-associated protein 2 kinase
p44-ERK1
Gene names
Name: MAPK3
Synonyms: ERK1, PRKM3

Function

Mitogen-activated protein kinase 4

Short name=MAP kinase 4
Short name=MAPK 4
EC=2.7.11.24
Alternative name(s):
Extracellular signal-regulated kinase 4
Short name=ERK-4
MAP kinase isoform p63
Short name=p63-MAPK
Gene names
Name: MAPK4
Synonyms: ERK4, PRKM4

Function

Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK4/MAPK4 is phosphorylated at Ser-186 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK4/MAPK4. May promote entry in the cell cycle By similarity.

Mitogen-activated protein kinase 6

Short name=MAP kinase 6
Short name=MAPK 6
EC=2.7.11.24
Alternative name(s):
Extracellular signal-regulated kinase 3
Short name=ERK-3
MAP kinase isoform p97
Short name=p97-MAPK

Function

Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK3/MAPK6 is phosphorylated at Ser-189 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6. May promote entry in the cell cycle By similarity.

Protein names Recommended name:

Mitogen-activated protein kinase 7
Short name=MAP kinase 7
Short name=MAPK 7
EC=2.7.11.24
Alternative name(s):
Big MAP kinase 1
Short name=BMK-1
Extracellular signal-regulated kinase 5
Short name=ERK-5
Gene names
Name: MAPK7
Synonyms: BMK1, ERK5, PRKM7

Function

Plays a role in various cellular processes such as proliferation, differentiation and cell survival. The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras-independent and MAP2K5-dependent pathway. May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction.

Mitogen-activated protein kinase 12

Short name=MAP kinase 12
Short name=MAPK 12
EC=2.7.11.24
Alternative name(s):
Extracellular signal-regulated kinase 6
Short name=ERK-6
Mitogen-activated protein kinase p38 gamma
Short name=MAP kinase p38 gamma
Stress-activated protein kinase 3

Function

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.