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.
Ran WeiXuguang LiuCourtney VossWentao QinLina DagninoLei LiMarc VignyShawn Shun-Cheng Li
Abstract:Stroke is currently the second leading cause of mortality and adult disability in the world.It expects to increase dramatically over the coming years.Stroke and its related illnesses cost the healthcare system billions of dollars each year worldwide,thus causing significant financial burden and economic hardship in the world.The disabilities afflicted in stroke survivors have also created significant social and economic impacts on societies worldwide.It is thus imperative that medical researchers develop effective treatment strategies in order to meet this today's challenge.Presently,even the cellular and molecular mechanisms of stroke are better understood,the effective treatment for stroke is still very limited.This has led stroke researchers to pursue different neuroprotective strategies aiming non-glutamate mechanisms to prevent neuronal damage and to promote neuronal survival,regeneration and functional recovery in stroke,thus offering potentially long-term economic,social,and healthcare benefits worldwide.
