MAMMALIAN NUMB IS AN EVOLUTIONARILY CONSERVED SIGNALING ADAPTER PROTEIN THAT SPECIFIES CELL FATE

Background: Drosophila numb was originally described as a mutation aff ecting binary divisions in the sensory organ precursor (SOP) lineage. The numb gene was subsequently shown to encode an asymmetrically local ized protein which is required for binary cell-fate decisions during p eripheral nervous system development. Part of the Drosophila NUMB prot ein exhibits homology to the SHC phosphotyrosine-binding (PTB) domain, suggesting a potential link to tyrosine-kinase signal transduction. R esults: A widely expressed mammalian homologue of Drosophila numb (dnu mb) has been cloned from rat and is referred to here as mammalian Numb (mNumb), The mNUMB protein has a similar overall structure to dNUMB a nd 67% sequence similarity, Misexpression of mNumb in Drosophila durin g sensory nervous system precursor cell division causes identical cell fate transformations to those produced by ectopic dNUMB expression. i n vitro, the mNUMB PTB domain binds phosphotyrosine-containing protein s, and SH3 domains of SRC-family tyrosine kinases bind to mNUMB presum ably through interactions with proline-rich regions in the carboxyl te rminus. Overexpression of full-length mNUMB in the multipotential neur al crest stem cell line MONO-1 dramatically biases its differentiation towards neurons, whereas overexpression of the mNUMB PTB domain biase s its differentiation away from neuronal fates. Conclusions: Our resul ts demonstrate that mNUMB is an evolutionarily conserved functional ho mologue of dNUMB, and establish a link to tyrosine-kinase-mediated sig nal transduction pathways. Furthermore, our results suggest that mNUMB and dNUMB are new members of a family of signaling adapter molecules that mediate conserved cell-fate decisions during development.