Signaling by ALK

Stable Identifier
Homo sapiens
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The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that was discovered as an oncogene in anaplastic large cell lymphomas, but also plays an oncogenic role in other cancer types, such as non-small-cell lung cancer (NSCLC), neuroblastoma and glioblastoma. The activation of anaplastic lymphoma kinase (ALK) requires the binding of the ligand pleiotrophin (PTN) or midkine (MDK), which induces the dimerization of the receptor. ALK dimers undergo trans-autophosphorylation, resulting in a fully activated receptor that triggers downstream signaling cascades such as RAS signaling, PI3K signaling and IRS1 signaling. In cancer, ALK gene frequently undergoes translocation, resulting in formation of fusion ALK proteins, such as NPM-ALK and EML4-ALK. These fusion proteins consist of the C-terminal region of ALK, with the kinase domain and the effector protein binding domain, while the N-terminus contains the dimerization domain of the ALK fusion partner. Fusion proteins of ALK are therefore capable of ligand-independent dimerization, resulting in constitutive ALK signaling. ALK can also undergo ligand-independent activation through RPTPB/RPTPZ.

ALK gene is mainly expressed in the developing central and peripheral nervous system. PTN and MDK have neuroprotective effect against neurotoxic agents and in neurodegenerative diseases.

For review, please refer to Chiarle et al. 2008, Wellstein 2012, Deuel 2013, Hallberg and Palmer 2013, Kadomatsu et al. 2013, Winkler and Yao 2014, Herradon and Perez-Garcia 2014, Janoueix-Lerosey et al. 2018, Della Corte et al, 2018.

Literature References
PubMed ID Title Journal Year
23267434 ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers

Wellstein, A

Front Oncol 2012
29374774 The ALK receptor in sympathetic neuron development and neuroblastoma

Lopez-Delisle, L, Delattre, O, Rohrer, H, Janoueix-Lerosey, I

Cell Tissue Res. 2018
24060861 Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

Palmer, RH, Hallberg, B

Nat. Rev. Cancer 2013
23889475 Targeting midkine and pleiotrophin signalling pathways in addiction and neurodegenerative disorders: recent progress and perspectives

Herradón, G, Pérez-García, C

Br. J. Pharmacol. 2014
23777859 Anaplastic lymphoma kinase: "Ligand Independent Activation" mediated by the PTN/RPTPβ/ζ signaling pathway

Deuel, TF

Biochim. Biophys. Acta 2013
23625998 The heparin-binding growth factor midkine: the biological activities and candidate receptors

Tsubota, S, Kadomatsu, K, Kishida, S

J. Biochem. 2013
18097461 The anaplastic lymphoma kinase in the pathogenesis of cancer

Chiarle, R, Piva, R, Ambrogio, C, Inghirami, G, Voena, C

Nat. Rev. Cancer 2008
24125182 The midkine family of growth factors: diverse roles in nervous system formation and maintenance

Winkler, C, Yao, S

Br. J. Pharmacol. 2014
29455642 Role and targeting of anaplastic lymphoma kinase in cancer

Troiani, T, Viscardi, G, Morgillo, F, Fasano, M, Martinelli, E, Ciardiello, F, Della Corte, CM, Di Liello, R

Mol. Cancer 2018
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