ALK tyrosine kinase receptor

UniProt Q9UM73 Organism Homo sapiens Gene ALK EC 2.7.10.1

Also known as: ALK

Function

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. Also acts as a key thinness protein involved in the resistance to weight gain: in hypothalamic neurons, controls energy expenditure acting as a negative regulator of white adipose tissue lipolysis and sympathetic tone to fine-tune energy homeostasis (By similarity). Following activation by ALKAL2 ligand at the cell surface, transduces an extracellular signal into an intracellular response. In contrast, ALKAL1 is not a potent physiological ligand for ALK. Ligand-binding to the extracellular domain induces tyrosine kinase activation, leading to 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. Induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. ALK activation may also be regulated by pleiotrophin (PTN) and midkine (MDK). 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. May function as regulator of gastric epithelial differentiation (By similarity).

Classification

Family (Pfam): PF12810 ALK_LTK_GRD, PF00629 MAM, PF07714 PK_Tyr_Ser-Thr
InterPro: ALK/LTK-like_GRD, ConA-like_dom_sf, Kinase-like_dom_sf, LDL_receptor-like_sf, LDrepeatLR_classA_rpt, MAM_dom, Prot_kinase_dom, Protein_kinase_ATP_BS, RTK, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_AS, Tyr_kinase_cat_dom, Tyr_kinase_rcpt_2_CS
Functional cluster: Secreted Growth Factors & Cytokines

Experimental structures · PDB · 79

2KUP NMR
2KUQ NMR
2XB7 X-ray 2.50A
2XBA X-ray 1.95A
2XP2 X-ray 1.90A
2YFX X-ray 1.70A
2YHV X-ray 1.90A
2YJR X-ray 1.90A
2YJS X-ray 1.90A
2YS5 NMR
2YT2 NMR
3AOX X-ray 1.75A
… and 67 more

A predicted model is available from AlphaFold.

Gene Ontology · 22

Disease associations

neuroblastoma, susceptibility to, 3 MONDO:0013083

Drugs targeting this protein · 10

ENTRECTINIB inhibitor
CERITINIB inhibitor
LORLATINIB inhibitor
BRIGATINIB inhibitor
ASP-3026 inhibitor
ALECTINIB HYDROCHLORIDE inhibitor
CONTELTINIB inhibitor
CEP-37440 inhibitor
ENSARTINIB inhibitor
CRIZOTINIB inhibitor

Related proteins · sequence + function similarity

ALK tyrosine kinase receptor 0.99
ALK tyrosine kinase receptor 0.99
Tyrosine-protein kinase receptor 0.88
ALK tyrosine kinase receptor 0.84
Pappalysin-2 0.76
Apical endosomal glycoprotein 0.75
Apical endosomal glycoprotein 0.74
Apical endosomal glycoprotein 0.71
Pappalysin-1 0.71
Leukocyte tyrosine kinase receptor 0.71
Pappalysin-1 0.70
Proprotein convertase subtilisin/kexin type 9 0.69

Co-cited proteins · studied together in the literature

ALK tyrosine kinase receptor 4 shared papers
ALK tyrosine kinase receptor 1 shared papers
ALK and LTK ligand 2 4 shared papers
WD repeat and coiled-coil-containing protein 1 shared papers
Pleiotrophin 2 shared papers
Cysteine--tRNA ligase, cytoplasmic 1 shared papers
Echinoderm microtubule-associated protein-like 4 1 shared papers
Leukocyte tyrosine kinase receptor 2 shared papers
ALK and LTK ligand 1 2 shared papers
Protein transport protein Sec31A 1 shared papers
Midkine 1 shared papers
Insulin receptor substrate 1 2 shared papers

Literature · 38 cited papers

Mechanism for the activation of the anaplastic lymphoma kinase receptor. Nature · 2021
Structural basis of cytokine-mediated activation of ALK family receptors. Nature · 2021
ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation. EMBO J. · 2021
Identification of a biologically active fragment of ALK and LTK-Ligand 2 (augmentor-alpha). Proc. Natl. Acad. Sci. U.S.A. · 2018
Heparin is an activating ligand of the orphan receptor tyrosine kinase ALK. Sci. Signal. · 2015
The R1275Q neuroblastoma mutant and certain ATP-competitive inhibitors stabilize alternative activation loop conformations of anaplastic lymphoma kinase. J. Biol. Chem. · 2012
Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat. Med. · 2012
CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell · 2011
The constitutive activity of the ALK mutated at positions F1174 or R1275 impairs receptor trafficking. Oncogene · 2011
Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors. Biochemistry · 2010
Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain. Biochem. J. · 2010
Structural basis for the recognition of nucleophosmin-anaplastic lymphoma kinase oncoprotein by the phosphotyrosine binding domain of Suc1-associated neurotrophic factor-induced tyrosine-phosphorylated target-2. J. Struct. Funct. Genomics · 2010
… and 26 more in the literature graph

A document in the lmmol reference corpus — open public data (UniProt, GO, PDB, the literature graph) rendered as a single cross-linked page. Hover any link to preview its target.