NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner

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.

Citation

Ran Wei, Xuguang Liu, Courtney Voss, Wentao Qin, Lina Dagnino, Lei Li, Marc Vigny, Shawn Shun-Cheng Li, Haian Fu. NUMB regulates the endocytosis and activity of the anaplastic lymphoma kinase in an isoform-specific manner Journal of Molecular Cell Biology. 2019 Feb 06;11(11):994-1005

PMID: 30726988

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