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

ALK (Q9UM73) - Overview - Molecular Target Synopsis

Protein


ALK, ALK tyrosine kinase receptor
Enzyme Classification 2.7.10.1
UniProt Q9UM73

Also Known as ALK_HUMAN, ALK

Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK. Homodimer. Homodimerizes when bound to ligand. Interacts with FRS2, IRS1, MDK, PTN and SHC1. Interacts with CBL, PIK3R1 and PLCG1.

6E0R
HALK IN COMPLEX WITH COMPOUND 7 N-((1S)-1-(5-FLUOROPYRIDIN-2-YL) ETHYL)-1-(5-METHYL-1H-PYRAZOL-3-YL)-3-(OXETAN-3-YLSULFONYL)-1H- PYRROLO[2,3-B]PYRIDIN-6-AMINE
RCSB/PDB
Inspect Structure
See all 3D Structures for ALK

Isoforms / Transcripts (Protein Coding)


Drugs


ALK is targeted by Approved Drugs Alectinib Hydrochloride, Ceritinib, Crizotinib. (see details)
Alectinib Hydrochloride
Ceritinib
Crizotinib

Sub-cellular localization


UniProt: ALK is active in the following subcellular-locations: cell membrane.
GO terms: ALK is active in the following subcellular-locations: extracellular exosome, integral component of plasma membrane, plasma membrane, protein-containing complex, receptor complex.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project ALK has gain in 3 cell-lines, loss in 0 cell-lines and no signal in 1002 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: SR, RXF_393, UACC_257

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: SU-DHL-1, SR-786, SR

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: SK-N-SH_RA, SK-N-SH, NHLF

(see details)

RNA Interference


ALK was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: SKGT4, CAL72. (see details)

3D Structures


For ALK there are:
61 structures (63 chains) solved
47 are solved in complex with at least one small molecule ligand
11 are solved with an approved drug

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

EMH/ALECTINIB (3AOX_A),
COM/MESNA (4TT7_A),
VGH/CRIZOTINIB (2XP2_A, 2YFX_A, 4ANQ_A, 4ANS_A, 5AAA_A, 5AAB_A, 5AAC_A),
6GY/BRIGATINIB (6MX8_A),
4MK/CERITINIB (4MKC_A).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


ALK has been screened with 2208 compounds (3564 bioactivities), 1009 compounds have bioactivities that show binding affinity of <= 500nM (1471 bioactivities). (see details)