MAPK1, ERK: A Drug Target and Biomarker (G5594)

NCBI ID: G5594

MAPK1

MAPK1, ERK: A Drug Target and Biomarker

MAPK1, also known as ERK (extracellular signal-regulated kinase), plays a crucial role in various cellular processes, including injury sensing and repair. It can be activated by receptor tyrosine kinases and is involved in controlling cellular contraction, motility, and gene transcription. Calcium signaling and ERK signaling are interconnected, with calcium influencing ERK activation and vice versa.

In addition to its role in injury response, the ERK/MAPK signaling pathway is involved in both cell growth and death, depending on the cellular conditions. Activation of ERK1/2 promotes cell proliferation and survival in the presence of growth factors, while under oxidative stress, ER stress, and cytokine stimulation, other MAPK subgroups like p38 and JNK are activated, leading to apoptosis and inflammatory responses. Furthermore, the ERK1/2 pathway, closely associated with the MAPK signal transduction pathway, can protect cells against ER stress-induced cell death by reducing protein misfolding in the endoplasmic reticulum.

The MAPK signaling pathway is also involved in microbial recognition and immune responses. Animal and plant cells utilize different pattern recognition receptors (PRRs) to recognize pathogenic microorganisms. Animal cells rely on Toll-like receptors (TLRs), while plants employ nucleotide-binding domain and leucine-rich repeat superfamily proteins (NLRs). Activation of TLRs leads to the production of antimicrobial peptides and signaling molecules, such as cytokines and chemokines. Similarly, NLR proteins, such as NOD1 and NOD2, activate signaling pathways involving NF-kappaB and MAPKs, leading to the production of inflammatory factors.

Overall, MAPK1/ERK is a multifunctional protein involved in injury response, cell growth and death, as well as microbial recognition and immune responses. Its activation and signaling pathways are interconnected with calcium signaling and play vital roles in maintaining cellular homeostasis and coordinating various cellular behaviors .
ERK, also known as MAPK1, is a protein involved in signaling pathways that regulate various cellular processes. It can detach from MEK and either translocate to the nucleus, dimerize in the cytoplasm, or interact with specific scaffolds for sublocalization-specific functions. ERK signaling cascade starts with ligand stimulation, leading to the activation of receptor tyrosine kinases, Ras, Raf, and ultimately ERK activation. ERK phosphorylates cytoplasmic and nuclear substrates involved in cell fate determination.

ERK is also implicated in innate immunity in both animals and plants. Animal cells use pattern recognition receptors, adaptors, signaling pathways, and effectors to recognize and respond to pathogens. Similarly, plants employ cell surface receptors and intracellular receptors of the NLR superfamily. ERK signaling plays a role in these immune responses.

Moreover, researchers have developed methods to specifically modulate the activity of endogenous ERK using light or chemical triggers. By caging the phospho-lyase OspF, they can control ERK and p38 activity. Decaging OspF using light or a chemical trigger allows the removal of phosphate groups from specific residues on ERK and p38, permanently inactivating their activity.

In terms of feedback regulation, ERK signaling pathway has intrinsic mechanisms to exert negative feedback at each level. ERK can regulate its own pathway at various points through phosphoregulation and transcriptional regulation of negative regulators. One example is ERK-induced dephosphorylation of the MEK protein mediated by the phosphatases PP1 or PP2A, limiting further ERK activation [8,10].

Overall, ERK, or MAPK1, is a key protein involved in signaling pathways that regulate cell fate, innate immunity, and feedback regulation. Researchers have used innovative approaches to modulate and understand its activity in different contexts.

Protein Name: Mitogen-activated Protein Kinase 1

Functions: 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 also plays 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 FXR1) 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 response to EGF stimulation. May play a role in the spindle assembly checkpoint. Phosphorylates PML and promotes its interaction with PIN1, leading to PML degradation. Phosphorylates CDK2AP2 (By similarity)

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