Reactome | ALK binds ALKAL ligand

ALK binds ALKAL ligand

Stable Identifier

R-HSA-9842656

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, extracellular region

ReviewStatus

5/5

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Signaling through the ALK receptor is activated by the binding of ALKAL ligand to the receptor extracellular region (Zhang et al, 2014; Guan et al, 2015; Reshetnyak et al, 2015; Reshetnyak et al, 2018; Reshetnyak et al, 2021; De Munck et al, 2021).
There are two human ALKAL proteins, ALKAL1 (also known as FAM150A) and ALKAL2 (also known as FAM150B). ALKAL1 and 2 were initially characterized as ligands for the ALK-related receptor leukocyte tyrosine kinase (LTK), and subsequently shown to bind to ALK as well (Zhang et al, 2014; Guan et al, 2015). Further studies revealed differences in ligand affinity for the two receptors, however, likely mediated by the differences in the extracellular domains of the two receptors. Although LTK is potently activated by both ALKAL1 and 2, robust activation of ALK in physiological contexts is only seen with ALKAL2 (Guan et al, 2015; Reshetnyak et al, 2015).
There is conflicting evidence as to whether ALKAL2 binds ALK as a monomer ((De Munck et al, 2021) or a dimer (Reshetnyak et al, 2018; Reshetnyak et al 2021). In this pathway, ALKAL2 is depicted as binding ALK as a dimer linked by interchain disulphide bond at residue C66 (Reshetnyak et al, 2018; Reshetnyak et al, 2021). Binding of ALKAL2 to the ALK receptor is also facilitated by binding of heparin to ALK (De Munck et al, 2021).

Literature References

PubMed ID	Title	Journal	Year
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
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
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
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
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
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