Affinage

ALKAL1

ALK and LTK ligand 1 · UniProt Q6UXT8

Length
129 aa
Mass
14.3 kDa
Annotated
2026-06-09
26 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALKAL1 (FAM150A/AUG-β) is a secreted cytokine that functions as a high-affinity activating ligand for the receptor tyrosine kinase LTK, binding its extracellular domain with picomolar affinity (KD = 28 pM) to drive ligand-dependent receptor phosphorylation (PMID:25331893). It establishes a defined ligand hierarchy in which ALKAL1 preferentially activates LTK while only weakly engaging the related receptor ALK, in contrast to ALKAL2 which activates both (PMID:26630010); nonetheless ALKAL1 can bind and activate the ALK extracellular domain, including superactivating oncogenic ALK mutants (PMID:26418745, PMID:28030793). Structurally, ALKAL1 is a monomeric three-helix bundle cytokine that induces receptor dimerization with a 2:1 (ligand:receptor dimer) stoichiometry, tenting two receptors together and triggering a pronounced ligand-induced rearrangement of the receptor extracellular region into an orientation parallel to and stabilized against the membrane surface; the membrane-proximal EGF-like domain of the receptor dictates ALK-versus-LTK preference (PMID:34819673, PMID:34646012). Physiologically, ALKAL1 is required in vivo for iridophore development in zebrafish, acting specifically through Ltk rather than Alk (PMID:29078341). In pathological settings, ALKAL1 promotes ALK-driven BRAF-inhibitor resistance in melanoma via the PI3K/AKT pathway (PMID:31229894), drives colorectal cancer migration, invasion, and metastasis through Sonic Hedgehog signaling (PMID:33391411), and, as an AhR target gene in MerTK+ macrophages, facilitates MerTK phosphorylation to promote phagocytosis and an immunosuppressive tumor microenvironment (PMID:39365866).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2014 High

    Identified the orphan-receptor ligand for LTK, answering what activates this receptor tyrosine kinase and defining ALKAL1 as a bona fide functional ligand.

    Evidence Large-scale functional signaling screen of 3,191 extracellular proteins with binding affinity and LTK phosphorylation assays

    PMID:25331893

    Open questions at the time
    • Did not resolve binding stoichiometry or structural mode of receptor engagement
    • Downstream signaling pathways not delineated
  2. 2015 High

    Established the receptor selectivity of ALKAL1 versus ALKAL2, clarifying which receptor each ligand preferentially activates and resolving a ligand hierarchy across ALK and LTK.

    Evidence Cell-based binding and receptor activation assays plus NIH/3T3 transformation and Ba/F3 IL-3-independent growth assays

    PMID:26418745 PMID:26630010

    Open questions at the time
    • Structural basis of differential ALK/LTK preference not yet defined
    • Physiological relevance of weak ALK binding by ALKAL1 unclear
  3. 2017 High

    Demonstrated an in vivo physiological role, showing ALKAL1 is genetically required for iridophore development through Ltk, placing the ligand upstream of a specific receptor in a defined developmental process.

    Evidence Zebrafish genetic loss-of-function models with iridophore phenotyping and epistasis against Ltk-deficient fish

    PMID:29078341

    Open questions at the time
    • Mammalian developmental role not addressed
    • Downstream signaling from Ltk in iridophores not mapped
  4. 2017 Medium

    Showed ALKAL1 can activate cancer-associated ALK mutants in a ligand-dependent manner, distinguishing ligand-dependent from constitutively active oncogenic mutations.

    Evidence In vitro biochemical assays and Drosophila in vivo analyses with ALK inhibitor sensitivity testing

    PMID:28030793

    Open questions at the time
    • Single-lab study across model systems
    • Clinical relevance in thyroid cancer patients not established
  5. 2021 High

    Resolved the structural mechanism of receptor activation, defining ALKAL1 as a monomeric cytokine that drives 2:1 receptor dimerization and a membrane-proximal extracellular rearrangement, and identifying the determinant of receptor preference.

    Evidence Cryo-EM, NMR, and X-ray crystallography of human ALK/LTK extracellular complexes with structure-function mutagenesis

    PMID:34646012 PMID:34819673

    Open questions at the time
    • Full-length transmembrane/intracellular activation step not captured
    • Dynamics of membrane stabilization in cells not directly observed
  6. 2019 Medium

    Linked ALKAL1 to therapy resistance, showing it is necessary for ALK activation driving BRAF-inhibitor resistance via PI3K/AKT.

    Evidence Phospho-RTK arrays, FAM150A knockdown/overexpression, and PI3K/AKT readouts in melanoma cell culture and mouse xenografts

    PMID:31229894

    Open questions at the time
    • Single-lab study
    • Whether effect is LTK- or ALK-mediated not fully resolved
  7. 2021 Medium

    Connected ALKAL1 to a distinct oncogenic pathway, showing its tumor-promoting activity in colorectal cancer depends on Sonic Hedgehog signaling.

    Evidence siRNA silencing with migration/invasion assays, in vivo tumor assays, GSEA, and SHH luciferase reporters

    PMID:33391411

    Open questions at the time
    • Mechanistic link between receptor activation and SHH pathway not defined
    • Single-lab study
  8. 2024 Medium

    Revealed an immune-microenvironment role, showing ALKAL1 is an AhR target in macrophages that promotes MerTK phosphorylation and immunosuppressive polarization.

    Evidence Single-cell RNA-seq, adoptive transfer, AhR antagonist studies, and phosphorylation assays in melanoma models

    PMID:39365866

    Open questions at the time
    • Direct ALKAL1-MerTK binding not demonstrated
    • Single-lab study
  9. 2025 Medium

    Reconciled competing receptor dimerization models, confirming that LTK-ALKAL1 and ALK-ALKAL2 share a common 2:1 dimerization mode and that 2:1 and 2:2 assemblies coexist.

    Evidence Cryo-EM reanalysis of deposited EMPIAR-10930 data with particle rebalancing and Blush-regularized refinement

    PMID:40208865

    Open questions at the time
    • Single computational reanalysis
    • Functional consequence of coexisting stoichiometries in cells not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ALKAL1 receptor activation mechanistically couples to the divergent downstream programs (PI3K/AKT, SHH, MerTK) and the mammalian physiological function of the ligand remain unresolved.
  • No mammalian developmental loss-of-function phenotype reported in the corpus
  • Mechanistic link from receptor dimerization to SHH and MerTK pathways undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 1
Partners
ALKLTK

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 ALKAL1 (FAM150A) binds the extracellular domain of leukocyte tyrosine kinase (LTK) with high affinity (KD = 28 pM) and stimulates LTK phosphorylation in a ligand-dependent manner, establishing it as a functional ligand for LTK. Functional signaling screen of 3,191 extracellular proteins, binding affinity measurements, LTK phosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 25331893
2015 ALKAL1 (FAM150A/AUG-β) is specific for LTK and only weakly binds ALK, establishing a ligand hierarchy: ALKAL2 (FAM150B/AUG-α) activates both ALK and LTK, while ALKAL1 preferentially activates LTK. Detailed binding experiments using cells expressing ALK or LTK, receptor activation assays, NIH/3T3 transformation and Ba/F3 IL-3-independent growth assays Proceedings of the National Academy of Sciences of the United States of America High 26630010
2015 ALKAL1 (FAM150A) and ALKAL2 (FAM150B) are potent activating ligands for human ALK that bind to the extracellular domain of ALK and can drive 'superactivation' of activated ALK mutants from neuroblastoma. In vitro cell culture binding and activation assays, functional superactivation assays with neuroblastoma ALK mutants eLife High 26418745
2017 In zebrafish, ALKAL1 (aug-β) ligand is essential for iridophore development, and this function is mediated specifically through Ltk (not Alk); aug-α2 and aug-β are required for iridophore formation in the adult eye. Zebrafish genetic knockout/deficiency models, phenotypic analysis of iridophore patterning in embryonic and adult fish, epistasis with Ltk-deficient zebrafish Proceedings of the National Academy of Sciences of the United States of America High 29078341
2017 ALK-L1198F mutation (identified in anaplastic thyroid cancer) is not constitutively active but is activated by ALKAL1 (FAM150A/AUG-β) ligand in a ligand-dependent manner similar to wild-type ALK; ALK-G1201E shows only very weak activation by ALKAL1, likely due to impaired protein stability. In vitro cell culture biochemical assays, Drosophila in vivo analyses, ALK inhibitor sensitivity assays Oncotarget Medium 28030793
2021 Cryo-EM, NMR, and X-ray crystallography reveal that ALKAL1 acts as a monomeric ligand that induces ALK dimerization with 2:1 stoichiometry (one cytokine per two receptors), while ALKAL2 can act as a dimeric ligand enabling 2:2 assemblies; ALKAL1 causes the ALK extracellular region to undergo a pronounced ligand-induced rearrangement adopting an orientation parallel to the membrane surface, further stabilized by ligand-membrane interaction. Cryo-electron microscopy, NMR, X-ray crystallography, structural analysis of human ALK-ALKAL1/2 complexes Nature High 34819673
2021 X-ray crystal structures show ALKAL1 and ALKAL2 are monomeric three-helix bundle cytokines; their binding to ALK and LTK elicits dimeric 2:1 assemblies (one cytokine tenting two receptors) with two-fold symmetry proximal to the cell membrane; the membrane-proximal EGF-like domain of ALK dictates apparent cytokine preference between ALK and LTK. X-ray crystallography of ALK/LTK extracellular domains in complex with ALKAL1 and ALKAL2, structure-function mutagenesis Nature High 34646012
2025 Reanalysis of cryo-EM data confirms that both 2:1 and 2:2 ALK-ALKAL2 stoichiometric assemblies coexist in the same dataset; a 3.2 Å structure of the 2:1 ALK-ALKAL2 complex was resolved, reconciling ALK and LTK receptor dimerization modes and directly showing that LTK-ALKAL1 and ALK-ALKAL2 can share a common 2:1 receptor dimerization mode. Cryo-EM reanalysis (cryoSPARC particle rebalancing, RELION 3D refinement with Blush regularization) of deposited EMPIAR-10930 data PLoS biology Medium 40208865
2019 ALKAL1 (FAM150A) ligand is necessary for ALK activation in BRAF inhibitor-resistant melanoma; ALK activates the PI3K/AKT pathway to confer BRAFi resistance. Phospho-RTK array, FAM150A knockdown/overexpression, PI3K/AKT pathway analysis in cell culture and mouse xenograft models iScience Medium 31229894
2021 ALKAL1 silencing inhibits tumorigenesis, metastasis, and invasion of colorectal cancer cells via suppression of the Sonic Hedgehog (SHH) signaling pathway, which is essential for ALKAL1-induced migration. siRNA gene silencing, in vitro migration/invasion assays, in vivo tumor assays, GSEA, Western blotting, luciferase reporter assays for SHH pathway Journal of Cancer Medium 33391411
2024 ALKAL1 is a target gene of aryl hydrocarbon receptor (AhR) in MerTK+ macrophages and facilitates MerTK phosphorylation, resulting in heightened phagocytic activity and polarization toward an immunosuppressive phenotype in the melanoma tumor microenvironment. Single-cell RNA sequencing, adoptive transfer experiments, mechanistic studies with AhR antagonist, phosphorylation assays Science advances Medium 39365866

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 5'-Heterogeneity in human progesterone receptor transcripts predicts a new amino-terminal truncated "C"-receptor and unique A-receptor messages. Molecular endocrinology (Baltimore, Md.) 130 2082185
2015 Augmentor α and β (FAM150) are ligands of the receptor tyrosine kinases ALK and LTK: Hierarchy and specificity of ligand-receptor interactions. Proceedings of the National Academy of Sciences of the United States of America 117 26630010
2015 FAM150A and FAM150B are activating ligands for anaplastic lymphoma kinase. eLife 116 26418745
2012 Single-CpG-resolution methylome analysis identifies clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas. Carcinogenesis 105 22610075
2017 Alk and Ltk ligands are essential for iridophore development in zebrafish mediated by the receptor tyrosine kinase Ltk. Proceedings of the National Academy of Sciences of the United States of America 61 29078341
2021 Mechanism for the activation of the anaplastic lymphoma kinase receptor. Nature 50 34819673
2014 Deorphanization of the human leukocyte tyrosine kinase (LTK) receptor by a signaling screen of the extracellular proteome. Proceedings of the National Academy of Sciences of the United States of America 46 25331893
2021 Structural basis of cytokine-mediated activation of ALK family receptors. Nature 34 34646012
2020 Genome-Wide Analysis of Cell-Free DNA Methylation Profiling for the Early Diagnosis of Pancreatic Cancer. Frontiers in genetics 33 33424927
2022 The neuronal tyrosine kinase receptor ligand ALKAL2 mediates persistent pain. The Journal of clinical investigation 30 35608912
2017 Therapeutic strategies and mechanisms of drug resistance in anaplastic lymphoma kinase (ALK)-rearranged lung cancer. Pharmacology & therapeutics 28 28185914
2024 MerTK+ macrophages promote melanoma progression and immunotherapy resistance through AhR-ALKAL1 activation. Science advances 23 39365866
2018 Novel method for DNA methylation analysis using high-performance liquid chromatography and its clinical application. Cancer science 19 29520901
2019 Anaplastic Lymphoma Kinase Confers Resistance to BRAF Kinase Inhibitors in Melanoma. iScience 15 31229894
2018 Identification of a biologically active fragment of ALK and LTK-Ligand 2 (augmentor-α). Proceedings of the National Academy of Sciences of the United States of America 14 30061385
2017 Anaplastic lymphoma kinase L1198F and G1201E mutations identified in anaplastic thyroid cancer patients are not ligand-independent. Oncotarget 14 28030793
2023 Multifaceted Roles of ALK Family Receptors and Augmentor Ligands in Health and Disease: A Comprehensive Review. Biomolecules 11 37892172
2021 Biocompatible and antibacterial soy protein isolate/quaternized chitosan composite sponges for acute upper gastrointestinal hemostasis. Regenerative biomaterials 11 34221450
2021 ALKAL1 gene silencing prevents colorectal cancer progression via suppressing Sonic Hedgehog (SHH) signaling pathway. Journal of Cancer 10 33391411
2024 Molecular pathological approach to cancer epigenomics and its clinical application. Pathology international 9 38482965
1996 Pharmacoeconomic analysis of stress ulcer prophylaxis for critically ill patients. PharmacoEconomics 8 10160257
2019 Quantitative Proteome Reveals Variation in the Condition Factor of Sea Urchin Strongylocentrotus nudus during the Fishing Season Using an iTRAQ-based Approach. Marine drugs 3 31284417
2025 Genome-Wide Analysis of Genetic Predispositions Linked to Damaged Membranes and Impaired Fertility as Indicators of Compromised Sperm-Egg Interaction Mechanisms in Frozen-Thawed Rooster Semen. Frontiers in bioscience (Scholar edition) 2 40150870
2025 Anaplastic lymphoma kinase enhances Wnt signaling through R-spondin: A new dimension to ALK-mediated oncogenesis. International journal of biological macromolecules 1 40132715
2025 Reanalysis of cryo-EM data reveals ALK-cytokine assemblies with both 2:1 and 2:2 stoichiometries. PLoS biology 1 40208865
2025 Whole Exome Sequencing Reveals Novel Genetic Variants Associated with Atrial Septal Defect in a Tibetan Patient Cohort. Pharmacogenomics and personalized medicine 0 40955363

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