Abstract
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.
Highlights
Anaplastic lymphoma kinase (ALK) is a member of the orphan receptor tyrosine kinase (RTK) family
The phosphotyrosine binding (PTB) domain, which is capable of binding to a variety of different proteins, plays a critical role in NUMB function (Gulino et al, 2010)
To understand the mechanism underpinning the different functions of the two NUMB isoforms in ALK degradation and recycling, we examined their co-localizations with Rab4, Rab7, and Rab11, which were expressed as GFP-fused proteins in HEK293/ALK cells together with Flag-p66-NUMB or Flag-p72NUMB
Summary
Anaplastic lymphoma kinase (ALK) is a member of the orphan receptor tyrosine kinase (RTK) family. The ALK receptor is only transiently expressed in the nervous system during early developmental stages and maintained at a low level in adult tissue except for some neuronal cells (Morris et al, 1994). This gene is considered non-essential for development as only a mild.
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