Reactome | Signaling by ALK

Signaling by ALK

Stable Identifier

R-HSA-201556

DOI

10.3180/R-HSA-201556.4

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Click the image above or here to open this pathway in the Pathway Browser

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