ERK2

Official Full Name

mitogen-activated protein kinase 1

Organism

Homo sapiens

GeneID

5594

Background

This gene encodes 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 are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. The activation of this kinase requires its phosphorylation by upstream kinases. Upon activation, this kinase translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. One study also suggests that this protein acts as a transcriptional repressor independent of its kinase activity. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Two alternatively spliced transcript variants encoding the same protein, but differing in the UTRs, have been reported for this gene. [provided by RefSeq, Jan 2014]

Synonyms

ERK; p38; p40; p41; ERK2; ERT1; NS13; ERK-2; MAPK2; PRKM1; PRKM2; P42MAPK; p41mapk; p42-MAPK;

Bio Chemical Class

Kinase

Protein Sequence

MAAAAAAGAGPEMVRGQVFDVGPRYTNLSYIGEGAYGMVCSAYDNVNKVRVAIKKISPFEHQTYCQRTLREIKILLRFRHENIIGINDIIRAPTIEQMKDVYIVQDLMETDLYKLLKTQHLSNDHICYFLYQILRGLKYIHSANVLHRDLKPSNLLLNTTCDLKICDFGLARVADPDHDHTGFLTEYVATRWYRAPEIMLNSKGYTKSIDIWSVGCILAEMLSNRPIFPGKHYLDQLNHILGILGSPSQEDLNCIINLKARNYLLSLPHKNKVPWNRLFPNADSKALDLLDKMLTFNPHKRIEVEQALAHPYLEQYYDPSDEPIAEAPFKFDMELDDLPKEKLKELIFEETARFQPGYRS

Open

Disease

Allergic/hypersensitivity disorder, Arteries/arterioles disorder, Mature T-cell lymphoma, Melanoma, Pancreatic cancer, Rheumatoid arthritis, Solid tumour/cancer, Transplant rejection

Approved Drug

Clinical Trial Drug

8 +

Discontinued Drug

1 +

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Detailed Information

ERK is a serine/threonine protein kinase belonging to the members of Mitogen-Activated Protein Kinases (MAPKs). ERK is an important transduction protein that transmits mitogen signals in the body and is expressed in most cells. The current study found that ERK includes several subfamilies of ERK1/ERK2, ERK3/ERK4, and ERK5. Among them, ERK1/ERK2 is the earliest cloned member of the MAPKs family, collectively referred to as ERK1/2, with relative molecular masses of 42 kd and 44 kd, respectively. ERK1/2 is primarily activated by mitogen stimuli and subsequently leads to activation of a range of transcription factors that ultimately regulate cell proliferation and differentiation. ERK1/2 has up to 90% homology and is a proline-directed serine/threonine kinase. Like other MAPKs family kinases, activation of ERK1/2 requires the phosphorylation of serine (Y) and threonine (T) sites to be active.

Structure of ERK2

ERK includes two subtypes with up to 90% homology: ERK1 and ERK2. Although the two subtype sequences are similar, they all have their own independent functions, and ERK2 can well compensate for the functional defects of ERK1. For example, mice that knock out ERK2 cause embryo death. Like many kinases, ERK contains a long chain of polypeptides whose N-terminus and C-terminus are mutually curled to form a typical bilobal structure.

When MEK activates ERK, it first phosphorylates its N-terminal Thr183 and Tyr185 sites, and then causes a conformational change near the N-terminus and ATP-binding site. This effect is transmitted to the C-terminus such that the C-terminal active site binds to the substrate protein to phosphorylate its serine/threonine residue. The special property of ERK diphosphorylation is determined by a cyclic structure called Loop 12 in its molecule. The ring is located on the surface of the molecule and adjacent to the active site, some of which form a lip-like structure called the "phosphorylated lip." This region is considered to be a key structure that determines the activity of ERK protein kinases.

Although ERK1 and ERK2 have many similarities, they have different functions. ERK1, which knocks out fibroblasts, increases ERK2-dependent signaling and promotes cell proliferation while knocking out ERK2 completely inhibits cell proliferation. It is suggested that ERK2 can promote cell proliferation, while ERK1 plays a negative regulatory role on ERK2. Hamilton et al. showed that ERK2 leads to instability of ES cell self-renewal by reducing the expression of pluripotency genes (such as Nanog), but it is not particularly needed in the early stages of germ layer specification. Okazaki et al. established a demyelinating mouse model and showed that Erk2 activation in astrocytes plays a crucial role in aggravating demyelinating inflammation by inducing inflammatory mediators and gliosis. Therefore, therapy targeting Erk2 function in glial cells may be a promising approach to the treatment of different demyelinating diseases.

Activation Mechanism of ERK1/2

The activated MEK can bind to ERKs through its N-terminal region, catalyzing the bispecific phosphorylation of the Try and Thr residues in the ETY sub-function region "TEY box" and activating ERK. MEKs are not only the activator of ERKs but also the anchor of ERK in the cytoplasm, which fixes ERK in the cytosol when the signaling pathway is not activated. Studies have shown that ERK2 phosphorylates ERK2 and phosphorylates or unphosphorylated ERK2 to form a homodimer translocation into the nucleus, indicating that homodimers are an essential form of ERK entry into the nucleus. When the signal stimulates phosphorylation and dimerization of ERKs, it transfers the activated ERKs to the nucleus or other activation site, further phosphorylating the downstream substrate.

ERK2 and Cancer

Studies have shown that ERK2 gene amplification in humans is the cause of tumor resistance in cancer treatment. The ERK pathway is also over-activated in many cancers. Amplification of the ERK2 gene was found in tumor patients treated with anti-EGF receptor kinase inhibitors. Studies have suggested that this amplification contributes to the treatment of resistance. Bcl3 exists in the form of phosphoproteins in many cancer cells. Wang et al. showed that Bcl3 promotes its nuclear localization and stability through phosphorylation of IKK1/2, Akt and Erk2. It is shown that Bcl3 can link Akt, MAPK and NF-κB pathway, and provide a mechanism for how Bcl3 acts as an oncoprotein.

ERK2 Figure 1. Bcl3 phosphorylation by akt, erk2, and ikk. (Wang, et al. 2017)

ERK2 and multiple sclerosis (MS)

Activation of the ERK1/2 pathway can activate astrocytes, MG, T cells, macrophages, etc., releasing a variety of inflammatory factors, causing myelin damage, leading to the onset of MS and experimental autoimmune encephalomyelitis(EAE). A number of studies have shown that inhibition of the ERK1/2 pathway can reduce the release of inflammatory factors, reduce myelin damage, and improve the condition of MS/EAE, providing an important target for the development of MS drugs. In vitro experiments showed that lipopolysaccharide (LPS) can activate N9 cells by inducing phosphorylation of ERK2, and increase the expression of inducible nitric oxide synthase (iNOS) mRNA and protein, releasing an excess of nitric oxide (NO). The release of excess NO from microglia (MG) in the brain is associated with the onset of MS. LPS also activates MG via the ERK pathway, which promotes the production of TNF-α, IL-1β, and IL-6 at the RNA level, leading to the onset of MS/EAE.

References:

Hamilton, W. B., Kaji, K., & Kunath, T. (2013). Erk2 suppresses self-renewal capacity of embryonic stem cells, but is not required for multi-lineage commitment. Plos One, 8(4), e60907.
Roser, B., Jacques, P., & Philippe, L. (2016). Erk1 and erk2 map kinases: specific roles or functional redundancy?:. Frontiers in Cell & Developmental Biology, 4(fov035).
Okazaki, R., Doi, T., Hayakawa, K., Morioka, K., Imamura, O., & Takishima, K., et al. (2016). The crucial role of erk2 in demyelinating inflammation in the central nervous system. Journal of Neuroinflammation, 13(1), 235.
Wang, V. Y., Li, Y., Kim, D., Zhong, X., Du, Q., & Ghassemian, M., et al. (2017). Bcl3 phosphorylation by akt, erk2, and ikk is required for its transcriptional activity. Molecular Cell, 67(3).
Schwebs, D. J., Pan, M., Adhikari, N., Kuburich, N. A., Jin, T., & Hadwiger, J. A. (2018). Dictyostelium erk2 is an atypical mapk required for chemotaxis. Cellular Signalling, 46, 154-165.

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