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

MAP2K1 (Q02750) - Overview - Molecular Target Synopsis

Protein


MAP2K1, Dual specificity mitogen-activated protein kinase kinase 1
Enzyme Classification 2.7.12.2
UniProt Q02750

Also Known as MP2K1_HUMAN, MAP2K1, MEK1, PRKMK1

Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2K2/MEK2 function specifically in the MAPK/ERK cascade, and catalyze the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in the extracellular signal-regulated kinases MAPK3/ERK1 and MAPK1/ERK2, leading to their activation and further transduction of the signal within the MAPK/ERK cascade. Depending on the cellular context, this pathway mediates diverse biological functions such as cell growth, adhesion, survival and differentiation, predominantly through the regulation of transcription, metabolism and cytoskeletal rearrangements. One target of the MAPK/ERK cascade is peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that promotes differentiation and apoptosis. MAP2K1/MEK1 has been shown to export PPARG from the nucleus. The MAPK/ERK cascade is also involved in the regulation of 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. Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3/ERK1 and RGS14. Forms a heterodimer with MAP2K2/MEK2. Forms heterodimers with KSR2 which further dimerize to form tetramers. Interacts with ARBB2, LAMTOR3, MAPK1/ERK2, MORG1 and RAF1 (By similarity). Interacts with PPARG and with isoform 1 of VRK2 (PubMed:20679487, PubMed:17101779). Interacts with Yersinia yopJ (PubMed:16728640). Interacts with SGK1 (PubMed:19447520). Interacts with BIRC6/bruce (PubMed:18329369). Interacts with KSR1 (PubMed:10409742). Interacts with KAT7; the interaction promotes KAT7 phosphorylation.

5YT3
STRUCTURE OF THE HUMAN MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1 S218D AND S222D MUTANT
RCSB/PDB
Inspect Structure
See all 3D Structures for MAP2K1

Isoforms / Transcripts (Protein Coding)


Protein Length Ensembl Gene Ensembl Transcript Ensembl Protein Uniprot Isoform
393ENSG00000169032ENST00000307102ENSP00000302486Q02750-1
367Q02750-2
217ENSG00000169032ENST00000566326ENSP00000456438

Drugs


MAP2K1 is targeted by Approved Drugs Trametinib, Cobimetinib. (see details)
Trametinib
Cobimetinib

Sub-cellular localization


UniProt: MAP2K1 is active in the following subcellular-locations: centrosome, cytoplasm, cytoskeleton, membrane, microtubule organizing center, nucleus, spindle pole body.
GO terms: MAP2K1 is active in the following subcellular-locations: cytoplasm, cytosol, early endosome, endoplasmic reticulum, focal adhesion, Golgi apparatus, late endosome, microtubule organizing center, mitochondrion, nucleus, plasma membrane.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project MAP2K1 has gain in 2 cell-lines, loss in 1 cell-lines and no signal in 1002 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: HT29, NCI_H322M, U251

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: NCI-H322T, EBC-1, LXFL529

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: HMEC, HSMM, NHLF

(see details)

RNA Interference


MAP2K1 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: OVISE, HEC1A. (see details)

3D Structures


For MAP2K1 there are:
41 structures (51 chains) solved
41 are solved in complex with at least one small molecule ligand
2 are solved with an approved drug

MAP2K1 is solved in complex with the approved drug(s):

EUI/COBIMETINIB (4AN2_A, 4LMN_A).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


MAP2K1 has been screened with 1962 compounds (3053 bioactivities), 510 compounds have bioactivities that show binding affinity of <= 500nM (699 bioactivities). (see details)