NUMB-ASSOCIATED KINASE INTERACTS WITH THE PHOSPHOTYROSINE BINDING DOMAIN OF NUMB AND ANTAGONIZES THE FUNCTION OF NUMB IN-VIVO

During asymmetric cell division, the membrane-associated Numb protein localizes to a crescent in the mitotic progenitor and is segregated pr edominantly to one of the two daughter cells, We have identified a put ative serine/threonine kinase, Numb-associated kinase (Nak), which int eracts physically with the phosphotyrosine binding (PTB) domain of Num b, The PTB domains of Shc and insulin receptor substrate bind to an NP XY motif which is not present in the region of Nak that interacts with Numb PTB domain. We found that the Numb PTB domain but not the Shc PT B domain interacts with Nak through a peptide of II amino acids, impli cating a novel and specific protein-protein interaction, Overexpressio n of Nak in the sensory organs causes both daughters of a normally asy mmetric cell division to adopt the same cell fate, a transformation si milar to the loss of numb function phenotype and opposite the cell fat e transformation caused by overexpression of Numb, The frequency of ce ll fate transformation is sensitive to the numb gene dosage, as expect ed from the physical interaction between Nak and Numb. These findings indicate that Nak may play a role in cell fate determination during as ymmetric cell divisions.