Signaling by ALK

Stable Identifier
Homo sapiens
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The anaplastic lymphoma kinase (ALK) is a transmembrane receptor tyrosine kinase that, along with related receptor LTK (leukocyte tyrosine kinase receptor) is a member of the insulin receptor superfamily (Iwahara et al, 1997). ALK was discovered as an oncogene in anaplastic large cell lymphomas (ALCLs), but also plays an oncogenic role in other cancer types, such as non-small-cell lung cancer (NSCLC), inflammatory myofibroblastic tumours (IMT), melanoma, neuroblastoma and glioblastoma. In cancer, the chromosomal region encoding ALK frequently undergoes genomic rearrangements, resulting in the formation of ALK fusion proteins, such as NPM‑ALK (the result of a translocation event, t(2;5)(p23;q35) which is predominant in ALCL) and EML4‑ALK (an inversion event on chromosome 2) (Morris et al, 1994; Couts et al, 2018). These fusion proteins consist of the C‑terminal region of ALK, encompassing the kinase domain and the effector protein binding domain (with loss of the transmembrane domain), while the N‑terminus of the fusion protein contains the dimerization domain of the partner gene. Fusion proteins of ALK are therefore capable of ligand‑independent dimerization, resulting in constitutive ALK signaling (reviewed in Duyster et al, 2001; Chiarle et al, 2008; Della Corte et al, 2018; Hallberg and Palmer, 2013; Hallberg and Palmer, 2016; Janoueix-Larousey et al, 2018; Ducray et al, 2019). Additionally, amplification of ALK and/or point mutations leading to its constitutive activation have been detected in neuroblastoma (reviewed in McDuff et al, 2011).

Many of the functional studies on ALK have been conducted in the context of oncogenic forms of the protein. In contrast, fewer studies have been conducted on the wild type protein under normal physiological conditions, and indeed, ALK was initially classed as an orphan receptor with no identified ligand. Two small heparin-binding growth factors, pleiotrophin (PTN) and midkine (MDK), were initially identified as potential ligands however subsequent studies failed to support this (Stoica et al, 2001; Stoica et al, 2002; Mathivet et al, 2007; Moog-Lutz et al, 2005; Motegi et al, 2004; reviewed in Wellstein et al, 2012; Winkler et al, 2014; Herradon and Perez-Garcia, 2014). More recently, ALKAL1 and ALKAL2 (also known as FAM150A and FAM150B) have been identified as ligands for both ALK and the related LTK receptor, albeit with differing potencies (Zhang et al, 2014; Guan et al, 2015; Reshetnyak et al, 2015; Reshetnyak et al, 2018; Fadeev et al, 2018; Reshetnyak et al, 2021; De Munck et al, 2021; Borenas et al, 2021; reviewed in Hallberg and Palmer, 2016). Whereas LTK receptor is potently activated by both ALKAL1 and ALKAL2, ALK is only weakly stimulated by ALKAL1 (Reshetnyak et al, 2015; Reshetnyak et al, 2018). Ligand binding induces the dimerization of the receptor and transautophosphorylation, resulting in a fully activated receptor that triggers downstream signaling cascades such as RAS, PI3K and IRS1 signaling. ALK may also undergo ligand-independent activation through RPTPB/RPTPZ (Deuel et al, 2013).

ALK is mainly expressed in the developing central and peripheral nervous system and plays a role in differentiation during development (Souttou et al, 2001; Gouzi et al, 2005; Degoutin et al, 2007). In Drosophila and mice, ALK is a thinness gene involved in the resistance to weight gain (Orthofer et al, 2020). Through activation of STAT3 targets, ALK also appears to play a role in response to ethanol (Hamada et al, 2021).

Literature References
PubMed ID Title Journal Year
15226403 ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth

Kotani, M, Motegi, A, Sakuraba, H, Fujimoto, J, Yamamoto, T

J. Cell. Sci. 2004
33411331 ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation

Lai, WY, Mendoza-Garcia, P, Koster, J, Gaarder, J, Masudi, T, El Wakil, A, Lind, DE, Borenäs, M, Palmer, RH, Witek, B, Umapathy, G, Johansson, M, Chuang, TP, Claeys, A, Van den Eynden, J, Fransson, S, Arefin, B, Guan, J, Hallberg, B

EMBO J 2021
26418745 FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase

Mendoza, P, Pfeifer, K, Mohammed, A, Wolfstetter, G, Palmer, RH, Halenbeck, R, Umapathy, G, Hsu, AW, Zhang, H, Hugosson, F, Guan, J, Hallberg, B, Yamazaki, Y

Elife 2015
27573755 The role of the ALK receptor in cancer biology

Hallberg, B, Palmer, RH

Ann Oncol 2016
11121404 Activation of anaplastic lymphoma kinase receptor tyrosine kinase induces neuronal differentiation through the mitogen-activated protein kinase pathway

Carvalho, NB, Raulais, D, Vigny, M, Souttou, B

J. Biol. Chem. 2001
18097461 The anaplastic lymphoma kinase in the pathogenesis of cancer

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

Nat. Rev. Cancer 2008
29054983 ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms

Shellman, YG, Christiansen, J, Couts, KL, Robinson, WA, Gonzalez, R, Pitts, TM, Murphy, D, Le, A, Bagby, SM, Doebele, RC, Multani, P, Medina, T, Turner, JA, Tentler, JJ, Amato, C, Chow-Maneval, E, Wells, K, Applegate, A, Tan, AC, Bemis, J, Rioth, MJ, Hintzsche, JD

Mol Cancer Ther 2018
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
24060861 Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology

Palmer, RH, Hallberg, B

Nat. Rev. Cancer 2013
29374774 The ALK receptor in sympathetic neuron development and neuroblastoma

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

Cell Tissue Res. 2018
17274988 ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation

Vigny, M, Degoutin, J, Gouzi, JY

FEBS Lett. 2007
12122009 Midkine binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types

Wellstein, A, Kuo, AH, Stoica, GE, Riegel, AT, Bowden, ET, Sale, EB, Powers, C

J. Biol. Chem. 2002
11607814 Translocations involving anaplastic lymphoma kinase (ALK)

Morris, SW, Bai, RY, Duyster, J

Oncogene 2001
30061385 Identification of a biologically active fragment of ALK and LTK-Ligand 2 (augmentor-α)

Tomé, F, Mohanty, J, Kaur, N, Ahmed, M, Schlessinger, J, Plotnikov, AN, Puleo, DE, Cinnaiyan, AM, Reshetnyak, AV, Lax, I, Poliakov, A

Proc Natl Acad Sci U S A 2018
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
15886198 Activation and inhibition of anaplastic lymphoma kinase receptor tyrosine kinase by monoclonal antibodies and absence of agonist activity of pleiotrophin

Brunet-de Carvalho, N, Bureau, J, Moog-Lutz, C, Frobert, Y, Vigny, M, Créminon, C, Degoutin, J, Gouzi, JY

J Biol Chem 2005
23777859 Anaplastic lymphoma kinase: "Ligand Independent Activation" mediated by the PTN/RPTPβ/ζ signaling pathway

Deuel, TF

Biochim. Biophys. Acta 2013
32442405 Identification of ALK in Thinness

Boehm, A, Harkany, T, Metspalu, A, Müller, S, Tietge, UJF, Arnold, C, Clark, T, Haubensak, W, Demetz, E, Lazovic, J, Kozieradzki, I, Kaczanowska, J, Gheldof, N, Hilbe, R, Leopoldi, A, Orthofer, M, Hagelkrüys, A, Hui, CC, Dou, Z, Amann, S, Neely, GG, Zopf, LM, Hager, J, Esterbauer, H, Penninger, JM, Pospisilik, JA, Wang, QP, Tretiakov, EO, Kuhn, V, Neumayr, C, Ticevic, M, Mägi, R, Nõukas, M, Novatchkova, M, Cronin, SJF, Kiefer, FW, Tancevski, I, Spirk, K, Lepamets, M, Cikes, D, Nagy, V, Jais, A, Valsesia, A

Cell 2020
31366041 The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis

Ducray, SP, Turner, SD, Garland, GD, Natarajan, K, Egger, G

Cancers (Basel) 2019
24125182 The midkine family of growth factors: diverse roles in nervous system formation and maintenance

Winkler, C, Yao, S

Br. J. Pharmacol. 2014
23267434 ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers

Wellstein, A

Front Oncol 2012
25331893 Deorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a signaling screen of the extracellular proteome

Bosch, E, Bray, TL, Wang, G, Kavanaugh, WM, Halenbeck, R, Lee, E, Liu, H, Hestir, K, Pao, LI, Hsu, AW, Brace, AD, Zhang, H, Zhou, A, Williams, LT, Wong, BR

Proc Natl Acad Sci U S A 2014
22086496 Assessment of the transforming potential of novel anaplastic lymphoma kinase point mutants

Turner, SD, McDuff, FK, Dalbay, M, Lim, SV

Mol Carcinog 2013
11278720 Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin

Wellstein, A, Caughey, DJ, Kuo, AH, Karavanov, A, Sunitha, I, Malerczyk, C, Aigner, A, Riegel, AT, Souttou, B, Stoica, GE, Wen, D

J Biol Chem 2001
26630010 Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand-receptor interactions

Bai, H, Mohanty, J, Tome, F, Shi, X, Schlessinger, J, Murray, PB, Gunel, M, Mo, ES, Reshetnyak, AV, Lax, I

Proc Natl Acad Sci U S A 2015
16317043 Role of the subcellular localization of ALK tyrosine kinase domain in neuronal differentiation of PC12 cells

Vigny, M, Brunet-de Carvalho, N, Moog-Lutz, C, Gouzi, JY

J Cell Sci 2005
33641239 Binge-like ethanol drinking activates anaplastic lymphoma kinase signaling and increases the expression of STAT3 target genes in the mouse hippocampus and prefrontal cortex

Mayfield, RD, Ferguson, LB, Lasek, AW, Maienschein-Cline, M, Krishnan, HR, Hamada, K

Genes Brain Behav 2021
8122112 Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma

Morris, SW, Dittmer, KG, Shapiro, DN, Kirstein, MN, Saltman, DL, Look, AT, Valentine, MB

Science 1994
34819673 Mechanism for the activation of the anaplastic lymphoma kinase receptor

Kalodimos, CG, Mohanty, J, Miller, DJ, Schlessinger, J, Reshetnyak, AV, Nourse, A, Lax, I, Sowaileh, M, Rossi, P, Myasnikov, AG

Nature 2021
29317532 ALKALs are in vivo ligands for ALK family receptor tyrosine kinases in the neural crest and derived cells

Nüsslein-Volhard, C, Serluca, F, Mendoza-Garcia, P, Pfeifer, K, Palmer, RH, Guan, J, Singh, AP, Fadeev, A, Irion, U, Wiessner, S

Proc Natl Acad Sci U S A 2018
17904822 In contrast to agonist monoclonal antibodies, both C-terminal truncated form and full length form of Pleiotrophin failed to activate vertebrate ALK (anaplastic lymphoma kinase)?

Vigny, M, Mathivet, T, Mazot, P

Cell Signal 2007
34646012 Structural basis of cytokine-mediated activation of ALK family receptors

Felix, J, Yoshimi, A, Mukohyama, J, Kurikawa, M, Provost, M, Bloch, Y, Savvides, SN, Abdel-Wahab, O, De Munck, S, Omori, I, Bazan, JF

Nature 2021
9053841 Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system

Bucay, N, Yamamoto, T, Iwahara, T, Wen, D, Cupples, R, Ratzkin, B, Fujimoto, J, Mori, S, Arakawa, T

Oncogene 1997
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