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Extracellular domai...
Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration
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Huang, H. (author)
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Gont, A. (author)
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Kee, L. (author)
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Dries, R. (author)
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Pfeifer, K. (author)
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Sharma, B. (author)
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Debruyne, D. N. (author)
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Harlow, M. (author)
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Sengupta, S. (author)
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- Guan, Jikui (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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Yeung, C. M. (author)
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Wang, W. C. (author)
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- Hallberg, Bengt, 1956 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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- Palmer, Ruth H., 1970 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
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Irwin, M. S. (author)
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George, R. E. (author)
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(creator_code:org_t)
- Elsevier BV, 2021
- 2021
- English.
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 36:2
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in similar to 10% of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor, which is aberrantly expressed in most non-mutated cases, is unclear. Both WT and mutant proteins undergo extracellular domain (ECD) cleavage. Here, we map the cleavage site to Asn654-Leu655 and demonstrate that cleavage inhibition of WT ALK significantly impedes NB cell migration with subsequent prolongation of survival in mouse models. Cleavage inhibition results in the downregulation of an epithelial-to-mesenchymal transition (EMT) gene signature, with decreased nuclear localization and occupancy of beta-catenin at EMT gene promoters. We further show that cleavage is mediated by matrix metalloproteinase 9, whose genetic and pharmacologic inactivation inhibits cleavage and decreases NB cell migration. Together, our results indicate a pivotal role forWTALK ECD cleavage in NB pathogenesis, which may be harnessed for therapeutic benefit.
Subject headings
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
Keyword
- ALK receptor tyrosine kinase neuroblastoma cleavage MMP-9 migration
- β-catenin
- epithelial-to-mesenchymal transition
- wild-type ALK
- extracellular domain
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Huang, H.
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Gont, A.
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Kee, L.
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Dries, R.
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Pfeifer, K.
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Sharma, B.
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show more...
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Debruyne, D. N.
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Harlow, M.
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Sengupta, S.
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Guan, Jikui
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Yeung, C. M.
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Wang, W. C.
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Hallberg, Bengt, ...
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Palmer, Ruth H., ...
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Irwin, M. S.
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George, R. E.
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Cell Biology
- Articles in the publication
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Cell Reports
- By the university
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University of Gothenburg