ERK2

MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. ERK is a versatile protein kinase that regulates many cellular functions. Growing evidence suggests that extracellular signal-regulated protein kinase 1/2 (ERK1/2) plays a crucial role in promoting cell death in a variety of neuronal systems, including neurodegenerative diseases. It is believed that the magnitude and the duration of ERK1/2 activity determine its cellular function. Activation of ERK1/2 are implicated in the pathophysiology of spinal cord injury (SCI). ERK2 signaling is a novel target associated with the deleterious consequences of spinal injury. ERK-2, also known as Mitogen-activated protein kinase 1 (MAPK1), is a member of the protein kinase superfamily and MAP kinase subfamily. MKP-3 is a dual specificity phosphatase exclusively specific to ERK2 for its substrate recognition and dephosphorylating activity. The activation of ERK2 requires its phosphorylation by upstream kinases. Upon activation, ERK2 translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. ERK2 is involved in both the initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors such as ELK1. ERK2 acts as a transcriptional repressor which represses the expression of interferon gamma-induced genes. Transcriptional activity is independent of kinase activity. The nuclear-cytoplasmic distribution of ERK2 is regulated in response to various stimuli and changes in cell context. Furthermore, the nuclear flux of ERK2 occurs by several energy- and carrier-dependent and -independent mechanisms. ERK2 has been shown to translocate into and out of the nucleus by facilitated diffusion through the nuclear pore, interacting directly with proteins within the nuclear pore complex, as well as by karyopherin-mediated transport. ERK2 interacts with the PDE4 catalytic unit by binding to a KIM (kinase interaction motif) docking site located on an exposed beta-hairpin loop and an FQF (Phe-Gln-Phe) specificity site located on an exposed alpha-helix. These flank a site that allows phosphorylation by ERK, the functional outcome of which is orchestrated by the N-terminal UCR1/2 (upstream conserved region 1 and 2) modules.

ERK2 Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>Mitogen-Activated Protein Kinase (MAPK)>>ERK2/MAPK1/MAPK2

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>Mitogen-Activated Protein Kinase (MAPK)>>ERK2/MAPK1/MAPK2

ERK2 Related Pathways

• EGFR Signaling Pathway
• TGF-beta Signaling
• VEGF Signaling

ERK2 Alternative Names

ERK2, MAPK1, MAPK2, ERK-2, MAPK 1, MAPK 2, ERK, ERT1, P42MAPK, p42-MAPK, PRKM1, PRKM2, p38, p40, p41, p41mapk [Homo sapiens]

Erk2, Mapk1, MAPK2, ERK-2, ERT1, MAPK 1, MAPK 2, ERK, PRKM2, Prkm1, p41mapk, p42mapk, p42-MAPK, 29030612K14Rik, AA407128, AU018647, C78273 [Mus musculus]

Summaries for ERK2

Entrez Gene summary for ERK2:

The protein encoded by MAPK1 gene is a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals, and ERK2 are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. The activation of ERK2 requires its phosphorylation by upstream kinases. Upon activation, ERK2 translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. Two alternatively spliced transcript variants encoding the same protein, but differing in the UTRs, have been reported for MAPK1 gene.

Wikipedia summary for ERK2:

Mitogen-activated protein kinase 1, also known as MAPK1, p42MAPK, and ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.

Human ERK2 Protein General Information

 

• Protein names: Extracellular signal-regulated kinase 2 , Short name=ERK2
• Sequence length: 360 AA.
• Domain: The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
• Sequence similarities: Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. Contains 1 protein kinase domain.
• Post-translational modification: Phosphorylated upon KIT and FLT3 signaling By similarity. Dually phosphorylated on Thr-185 and Tyr-187, which activates the enzyme. 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.
• Subcellular location: Nucleus. Cytoplasm › cytoskeleton › centrosome. Cytoplasm. Note: Phosphorylated DAPK1 promotes its cytoplasmic retention.
• Tissue specificity: Widely expressed.
• Involvement in disease: Note=A chromosomal aberration involving ERK2 is a cause of chronic myeloid leukemia. Translocation t(9;22)(q34;q11) with BCR. The translocation produces a BCR-ABL found also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
• Catalytic activity: ATP + a protein = ADP + a phosphoprotein.
• 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. Dephospphorylated and inactivated by DUSP3, DUSP6 and DUSP9. Inactivated by pyrimidylpyrrole inhibitors.
• Cofactor: Magnesium.
• 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 . MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation By similarity. Interacts with DCC .

General information above from UniProt

Function for ERK2 Protein

UniProtKB:

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. ERK2 participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK2 cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The the MAPK/ERK2 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/ERK2 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 additionnal cytosolic and nuclear targets, thereby extending the specificity of the cascade.

ERK2 acts as a transcriptional repressor. ERK2 binds to a [GC]AAA[GC] consensus sequence. ERK2 repress the expression of interferon gamma-induced genes. ERK2 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.

Genatlas:

• ERK2 phosphorylates nuclear targets, microtubule associated protein 2, myelin basic protein and ELK1
• ERK2 promotes entry in the cell cycle
• ERK2 activates DD5 and TPR
• activation of ERK2 is a key regulator of the increased transition to hypertrophic differentiation of the growth plate
• ERK2 may play a critical role in TSC progression through posttranslational inactivation of TSC2
• ERK2 regulates the proliferation of mesenchymal stem cells without affecting their mobilization and differentiation potential
• ERK2/MAPK3 have a crucial role in cardiac hypertrophy
• ERK2 plays essential roles in osteoblast differentiation and in supporting osteoclastogenesis
• MAPK3 and ERK2 drastically differ in their capability of crossing the nuclear envelope with MAPK3 being three times slower than ERK2
• ERK2 plays a key role in the regulation of apoptosis during retinal development
• ERK2 coordinates adhesion disassembly with WASF2 regulatory complex activation and actin polymerization to promote productive leading edge advancement during cell migration

Homology for human ERK2

• ortholog to Mapk1, Rattus norvegicus
• ortholog to Mapk1, Ms musculus
• ortholog to MAPK1, Pan troglodytes