| Structural highlights
Function
[SCD2_CAEEL] Probable tyrosine-protein kinase receptor which regulates the dauer/non-dauer developmental decision probably by controlling daf-3 transcriptional activity in parallel or together with the TGF-beta pathway (PubMed:11063683, PubMed:18674914). Regulates integration of conflicting sensory cues in AIA interneurons (PubMed:21414922). May act as a receptor for hen-1 (PubMed:18674914, PubMed:21414922). In AWA neurons, together with hen-1, plays a role in regulating olfactory adaptation by controlling the forgetting sensory responses to odorants such as diacetyl (PubMed:28924007).[1] [2] [3] [4]
Publication Abstract from PubMed
The proto-oncogene ALK encodes anaplastic lymphoma kinase, a receptor tyrosine kinase that is expressed primarily in the developing nervous system. After development, ALK activity is associated with learning and memory(1) and controls energy expenditure, and inhibition of ALK can prevent diet-induced obesity(2). Aberrant ALK signalling causes numerous cancers(3). In particular, full-length ALK is an important driver in paediatric neuroblastoma(4,5), in which it is either mutated(6) or activated by ligand(7). Here we report crystal structures of the extracellular glycine-rich domain (GRD) of ALK, which regulates receptor activity by binding to activating peptides(8,9). Fusing the ALK GRD to its ligand enabled us to capture a dimeric receptor complex that reveals how ALK responds to its regulatory ligands. We show that repetitive glycines in the GRD form rigid helices that separate the major ligand-binding site from a distal polyglycine extension loop (PXL) that mediates ALK dimerization. The PXL of one receptor acts as a sensor for the complex by interacting with a ligand-bound second receptor. ALK activation can be abolished through PXL mutation or with PXL-targeting antibodies. Together, these results explain how ALK uses its atypical architecture for its regulation, and suggest new therapeutic opportunities for ALK-expressing cancers such as paediatric neuroblastoma.
Structural basis for ligand reception by anaplastic lymphoma kinase.,Li T, Stayrook SE, Tsutsui Y, Zhang J, Wang Y, Li H, Proffitt A, Krimmer SG, Ahmed M, Belliveau O, Walker IX, Mudumbi KC, Suzuki Y, Lax I, Alvarado D, Lemmon MA, Schlessinger J, Klein DE Nature. 2021 Dec;600(7887):148-152. doi: 10.1038/s41586-021-04141-7. Epub 2021, Nov 24. PMID:34819665[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Inoue T, Thomas JH. Suppressors of transforming growth factor-beta pathway mutants in the Caenorhabditis elegans dauer formation pathway. Genetics. 2000 Nov;156(3):1035-46. doi: 10.1093/genetics/156.3.1035. PMID:11063683 doi:http://dx.doi.org/10.1093/genetics/156.3.1035
- ↑ Reiner DJ, Ailion M, Thomas JH, Meyer BJ. C. elegans anaplastic lymphoma kinase ortholog SCD-2 controls dauer formation by modulating TGF-beta signaling. Curr Biol. 2008 Aug 5;18(15):1101-9. doi: 10.1016/j.cub.2008.06.060. PMID:18674914 doi:http://dx.doi.org/10.1016/j.cub.2008.06.060
- ↑ Shinkai Y, Yamamoto Y, Fujiwara M, Tabata T, Murayama T, Hirotsu T, Ikeda DD, Tsunozaki M, Iino Y, Bargmann CI, Katsura I, Ishihara T. Behavioral choice between conflicting alternatives is regulated by a receptor guanylyl cyclase, GCY-28, and a receptor tyrosine kinase, SCD-2, in AIA interneurons of Caenorhabditis elegans. J Neurosci. 2011 Feb 23;31(8):3007-15. doi: 10.1523/JNEUROSCI.4691-10.2011. PMID:21414922 doi:http://dx.doi.org/10.1523/JNEUROSCI.4691-10.2011
- ↑ Kitazono T, Hara-Kuge S, Matsuda O, Inoue A, Fujiwara M, Ishihara T. Multiple Signaling Pathways Coordinately Regulate Forgetting of Olfactory Adaptation through Control of Sensory Responses in Caenorhabditis elegans. J Neurosci. 2017 Oct 18;37(42):10240-10251. doi: 10.1523/JNEUROSCI.0031-17.2017. , Epub 2017 Sep 18. PMID:28924007 doi:http://dx.doi.org/10.1523/JNEUROSCI.0031-17.2017
- ↑ Li T, Stayrook SE, Tsutsui Y, Zhang J, Wang Y, Li H, Proffitt A, Krimmer SG, Ahmed M, Belliveau O, Walker IX, Mudumbi KC, Suzuki Y, Lax I, Alvarado D, Lemmon MA, Schlessinger J, Klein DE. Structural basis for ligand reception by anaplastic lymphoma kinase. Nature. 2021 Dec;600(7887):148-152. doi: 10.1038/s41586-021-04141-7. Epub 2021, Nov 24. PMID:34819665 doi:http://dx.doi.org/10.1038/s41586-021-04141-7
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