Reference Detail

Ref Type

Journal Article

PMID

(34646012)

Authors

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

Title

Structural basis of cytokine-mediated activation of ALK family receptors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature	600	7887	2021 Dec	143-147	Nature

URL

Abstract Text

Anaplastic lymphoma kinase (ALK)1 and the related leukocyte tyrosine kinase (LTK)2 are recently deorphanized receptor tyrosine kinases3. Together with their activating cytokines, ALKAL1 and ALKAL24-6 (also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development7, cancer7-9 and autoimmune diseases10. Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain11, consistent with a metabolic role for Drosophila ALK12. Despite such functional pleiotropy and growing therapeutic relevance13,14, structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles, yet their binding to ALK and LTK elicits similar dimeric assemblies with two-fold symmetry, that tent a single cytokine molecule proximal to the cell membrane. We show that the membrane-proximal EGF-like domain dictates the apparent cytokine preference of ALK. Assisted by these diverse structure-function findings, we propose a structural and mechanistic blueprint for complexes of ALK family receptors, and thereby extend the repertoire of ligand-mediated dimerization mechanisms adopted by receptor tyrosine kinases.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
ALK	F856S	missense	gain of function	ALK F856S lies within the extracellular domain of the Alk protein (UniProt.org). F856S confers a gain of function to the Alk protein as demonstrated by increased cell proliferation in the absence of growth factor (PMID: 26032424, PMID: 34646012) and colony formation in culture (PMID: 26032424).
ALK	R753Q	missense	gain of function - predicted	ALK R753Q lies within the extracellular domain of the Alk protein (UniProt.org). R753Q results in increased cytokine-dependent growth in cell culture (PMID: 34646012), and therefore, is predicted to lead to a gain of Alk protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ALK R753Q	Advanced Solid Tumor	sensitive	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, Xalkori (crizotinib) inhibited growth of transformed cells expressing ALK R753Q in culture (PMID: 34646012).	34646012
ALK F856S	Advanced Solid Tumor	sensitive	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, Xalkori (crizotinib) inhibited growth of transformed cells expressing ALK F856S in culture (PMID: 34646012).	34646012