ERK5 Signaling
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ERK5 Signaling

ERK5 (also known as the BMK1(Big MAP Kinase-1)) is an atypical MAPK that can be activated in vivo by a variety of stimuli, including Serum, Growth factors including EGF (Epidermal Growth Factor), NGF (Nerve Growth Factor) and BDNF (Brain-Derived Neurotrophic Factor), GPCRs (G-Protein Coupled Receptors), Lysophosphatidic Acid, Neurotrophins and Phorbol ester and some Cellular stress such as Oxidative and Osmotic Shock. MAPK (Mitogen Activated Protein Kinase) cascades play important roles in many cellular processes including cell proliferation, differentiation, survival and apoptosis. They are also important for many physiological functions in several systems, including in developmental, immune and neuronal systems. At least 12 isoforms of MAPKs exist in mammalian cells, and these can be divided into 4 main groups, the classical MAPKs (ERK1 (Extracellular Signal-Regulated Kinase-1) and ERK2 (Extracellular Signal-Regulated Kinase-1)), JNKs (c-Jun Kinases), p38s (also referred to as SAPK2 (Stress-Activated Protein Kinase-2), SAPK3 (Stress-Activated Protein Kinase-3) and SAPK4 (Stress-Activated Protein Kinase-4) and atypical MAPKs such as ERK3 (Extracellular Signal-Regulated Kinase-3), ERK5 (Extracellular Signal-Regulated Kinase-5) and ERK8 (Extracellular Signal-Regulated Kinase-8). With the exception of ERK3, MAPKs are activated by dual phosphorylation on a Thr-Xaa-Tyr motif by a dual specificity MKK (MAPK Kinase). MKKs are in turn activated by a MKKK (MAPK Kinase Kinase), which are activated in response to appropriate extracellular signals. ERK5 shares sequence homology with ERK1 and ERK2, and contains a threonine and tyrosine TEY dual phosporylation motif similar to ERK1/2 . However, a molecular mass of approximately 100 kDa, a large C-terminus and unique 12 loop structure distinguish ERK5 from ERK1/2 and other members of the MAPK family. Upstream components of the ERK5 pathway include Ras , MEKK2 (MAP/ERK Kinase Kinase-2), MEKK3 (MAP/ERK Kinase Kinase-3), MEK5 (MAPK/ERK Kinase-5), c-Src and COT (Cancer Osaka Thyroid Oncogene).  Downstream targets for ERK5 include Connexin-43, RSK (Ribosomal-S6 Kinase), and the transcription factors MEF2A, MEF2C, and MEF2D (Myocyte Enhance Factor-2); SAP1A (Signaling lymphocytic Activation molecule associated Protein-1A); SGK (Serum/Glucocorticoid-Regulated Kinase) and PPAR-Gamma1 (Peroxisome Proliferative Activated Receptor-Gamma-1). Activation of ERK5 is reversed by dual-specificity Phosphatases-C 100 and MKP3 (MAP Kinase Phosphatase-3) which was previously thought to be specific for ERK1/2 (Ref.1, 2 & 3).

Mitogens including EGF and G-CSF (Granulocyte Colony-Stimulating Factor) transmit their growth promoting signals via ERK5. WNK1 (WNK Lysine deficient protein Kinase-1) is required for activation of ERK5 by EGF. EGF induced activation of ERK5 can also be mediated via c-Src and Ras .  Adaptor/scaffold protein LAD (Lck-Associated Adapter)/TSAd is required for EGF-induced ERK5 activation via Src. TSAd may be responsible for increasing the binding affinity between MEKK2 and MEK5, and for recruiting the MEKK2/ MEK5 complex to the receptor, thus activating ERK5. ERK5 activation by G-CSF is differentially regulated by PTKs (Protein Tyrosine Kinases) and PKC (Protein Kinase-C). Cytokines including LIF (Leukemia Inhibitory Factor) and CT1 induce the phosphorylation of GAB1 (GRB2-Associated Binder-1) and SHP2 (Tyrosine Phosphatase Shp2) at Thr residues, thereby leading to the association of GAB1 to SHP2 and the activation of ERK5. GAB1 is another adaptor protein implicated in mediating ERK5 activation in response to LIF via the Gp130 signal complex. GAB1/SHP2 interaction is crucial for LIF-induced elongation of cardiomyocytes via ERK5. The muscle specific PKA (Protein Kinase-A) anchoring protein mAKAP (A-Kinase Anchor Protein) also contributes to the transduction of the hypertrophic signal via ERK5 in cardiomyocytes. MEK5 and ERK5 interact with the PDE4D3 (Phosphodiesterase E4D3) and EPAC1 (cAMP-dependent Exchange factor for the small GTPase Rap1) to form a functional complex with PKA and mAKAP . ERK5-mediated PDE4D3 phosphorylation decreases cAMP catabolism. The subsequent rise in cAMP concentration activates EPAC1 that suppress LIF-induced ERK5 activation via Rap1 (Ref.2, 4 & 5).

ERK5 is also activated by Neurotrophic factors including BDNF, NGF and NT3/4 (Neurotrophins 3/4). NGF-induced activation of ERK5 is mediated via COT or MEKK3 and MEK5, whereas BDNF-induced ERK5 activation occurs via MEK5. ERK5 also contributes to the survival response of DRG (Dorsal Root Ganglion) neurones to NGF (Neuronal Growth Factor). TRKA (Tyrosine Kinase Receptor-A) receptors present at the surface of the extending Axon autophosphorylate following the binding of NGF. Phosphorylated TRKA receptors are internalized into a signaling endosome that is retrogradely transported from the extending axon to the cell body where it activates ERK5. ERK5 then initiates a phosphorylation cascade resulting in the activation of the transcription factor CREB (Ca++/cAMP Response Element Binding protein) that regulates the transcription of survival and pro-apoptotic genes. ERK5 does not directly phosphorylate CREB, but translocates into the nucleus and phosphorylate the Kinase RSK, which phosphorylate CREB in turn. Evidence that ERK5 contributes to mediating the survival of neurons in the central nervous system via the activation of the transcription factor MEF2 has also been reported. ERK5 is also activated by Stress like Sorbitol, H2O2 (Hydrogen Peroxide) and UV irradiation. H2O2 stimulation of ERK5 is mediated via c-Src tyrosine kinase and H2O2-mediated activation of ERK5 increases MEF2C DNA binding activity, a transcription factor that has been shown to be important for neuronal activity-dependent neuronal survival. GPCRs can also potently stimulate ERK5 through a mechanism that involves GN-AlphaQ and GN-Alpha13, independently of Rho , Rac1 and CDC42 (Cell Division cycle-42) (Ref. 6, 7 & 8).

Following its activation, ERK5 phosphorylate several nuclear and cytoplasmic targets. The transcription factors of the MEF family, MEF2A, MEF2C, and MEF2D are among the best-characterized substrates of ERK5. Phosphorylation of MEF2C by ERK5 enhances its transcriptional activity and subsequently leads to increased c-Jun gene expression. While MEF2D is a specific substrate of ERK5, MEF2A and MEF2C activities are controlled by both p38 MAPKs and ERK5. Other direct substrates of ERK5 include SAP1, and c-Myc. While the effect of phosphorylation of c-Myc by ERK5 remains unclear, ERK5-dependent phosphorylation of SAP1 enhances transcription via a serum response element that may be responsible for increasing expression of c-Fos. In addition to acting on the c-Fos promoter, the ERK5 signaling pathway stimulates the transcriptional activity of c-Fos and FRA1 (Fos-Related Antigen-1) by a mechanism that implicates a kinase lying downstream of ERK5, which could be RSK . Another substrate of ERK5 is SGK, a protein kinase that is closely linked to the G1/S transition of the cell cycle. The phosphorylation of SGK by ERK5 at serine 78 is required for mediating SGK activation and for promoting the entry of cells into S phase of the cell cycle in response to growth factor. The transcriptional activation of the Cyclin D1 gene, a key cell proliferation checkpoint, the deregulation of which is frequently associated with neoplastic transformation, has also been shown to be regulated by the ERK5 cascade. Other targets of ERK5 include BAD (Bcl2-Antagonist of Cell Death) and FoxO3A (Forkhead Box-O3A). Under stress conditions, the non-phosphorylated forms of BAD and FoxO3A translocate to the mitochondria and the nucleus where they increase CytoC (Cytochrome-C) release and FasL gene transcription, respectively. FasL-mediated Caspase activation constitutes a positive feedback loop that enhances stress induced-apoptosis. ERK5 induces the phosphorylation of BAD and FoxO3A by PKB-independent and dependent mechanisms, respectively. In both cases, phosphorylation provides a mechanism by which ERK5 sequesters the proteins in the cytoplasm by promoting their interaction with 14-3-3, thereby blocking their apoptotic effect. Efforts of many scientists in recent years have led to major progress in understanding the regulation of ERK5 and its function. The potentially crucial role of ERK5 in cancers and heart diseases make this cascade highly attractive for the development of new therapeutic strategies to treat pathological conditions that are resistant to current therapies (Ref.9, 10 & 11).