NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner
| Autor: | Lei Li, Courtney Voss, Lina Dagnino, Ran Wei, Shawn S.-C. Li, Marc Vigny, Wentao Qin, Xuguang Liu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Gene isoform
animal structures Nerve Tissue Proteins Cell fate determination recycling Endocytosis Pediatrics Receptor tyrosine kinase 03 medical and health sciences 0302 clinical medicine NUMB hemic and lymphatic diseases Genetics endocytosis Anaplastic lymphoma kinase Animals Drosophila Proteins Humans Protein Isoforms Anaplastic Lymphoma Kinase Amino Acid Sequence Molecular Biology 030304 developmental biology degradation 0303 health sciences Binding Sites biology Chemistry Kinase fungi Membrane Proteins isoform Cell Biology General Medicine Cell biology Juvenile Hormones Protein Transport ALK 030220 oncology & carcinogenesis Mitogen-activated protein kinase embryonic structures biology.protein Original Article hormones hormone substitutes and hormone antagonists Protein Binding |
| Zdroj: | Journal of Molecular Cell Biology Paediatrics Publications |
| ISSN: | 1759-4685 1674-2788 |
| Popis: | NUMB is an evolutionarily conserved protein that plays an important role in cell adhesion, migration, polarity, and cell fate determination. It has also been shown to play a role in the pathogenesis of certain cancers, although it remains controversial whether NUMB functions as an oncoprotein or tumor suppressor. Here, we show that NUMB binds to anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase aberrantly activated in several forms of cancer, and this interaction regulates the endocytosis and activity of ALK. Intriguingly, the function of the NUMB–ALK interaction is isoform-dependent. While both p66-NUMB and p72-NUMB isoforms are capable of mediating the endocytosis of ALK, the former directs ALK to the lysosomal degradation pathway, thus decreasing the overall ALK level and the downstream MAP kinase signal. In contrast, the p72-NUMB isoform promotes ALK recycling back to the plasma membrane, thereby maintaining the kinase in its active state. Our work sheds light on the controversial role of different isoforms of NUMB in tumorigenesis and provides mechanistic insight into ALK regulation. |
| Databáze: | OpenAIRE |
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