Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

MAPK1 (P28482) - Overview - Molecular Target Synopsis

Protein


MAPK1, Mitogen-activated protein kinase 1
Enzyme Classification 2.7.11.24
UniProt P28482

Also Known as MK01_HUMAN, MAPK1, ERK2, PRKM1, PRKM2

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. Phosphorylates CDK2AP2., 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. Binds both upstream activators and downstream substrates in multimolecular complexes. 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). Interacts with STYX. Interacts with CDK2AP2. Interacts with CAVIN4 (By similarity). Interacts with DUSP7; the interaction enhances DUSP7 phosphatase activity (PubMed:9788880).

6QAW
ERK2 MINI-FRAGMENT BINDING
RCSB/PDB
Inspect Structure
See all 3D Structures for MAPK1

Isoforms / Transcripts (Protein Coding)


Protein Length Ensembl Gene Ensembl Transcript Ensembl Protein Uniprot Isoform
360ENSG00000100030ENST00000398822, ENST00000215832ENSP00000381803, ENSP00000215832P28482-1
316ENSG00000100030ENST00000544786ENSP00000440842P28482-2

Sub-cellular localization


UniProt: MAPK1 is active in the following subcellular-locations: caveola, centrosome, cytoplasm, cytoskeleton, membrane, microtubule organizing center, nucleus, spindle.
GO terms: MAPK1 is active in the following subcellular-locations: axon, azurophil granule lumen, caveola, cytoplasm, cytoskeleton, cytosol, dendrite cytoplasm, early endosome, extracellular region, ficolin-1-rich granule lumen, focal adhesion, Golgi apparatus, late endosome, microtubule organizing center, mitochondrion, mitotic spindle, nucleoplasm, nucleus, perikaryon, plasma membrane, postsynaptic density, protein-containing complex, pseudopodium.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project MAPK1 has gain in 8 cell-lines, loss in 1 cell-lines and no signal in 996 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: K_562, HS578T, SK_MEL_28

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: SNU-182, CAL-12T, VMRC-LCD

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: NHLF, HSMM, K562

(see details)

RNA Interference


MAPK1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: SUM44, ZR7530. (see details)

3D Structures


For MAPK1 there are:
100 structures (116 chains) solved
92 are solved in complex with at least one small molecule ligand
1 are solved with an approved drug

MAPK1 is solved in complex with the approved drug(s):

BEZ/BENZOIC ACID (5WP1_A).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


MAPK1 has been screened with 4032 compounds (6520 bioactivities), 1096 compounds have bioactivities that show binding affinity of <= 500nM (1628 bioactivities). (see details)