Functional analysis of the Numb phosphotyrosine-binding domain using site-directed mutagenesis.

The Journal of Biological Chemistry
L YaichB Margolis

Abstract

The Numb protein is involved in cell fate determination during Drosophila neural development. Numb has a protein domain homologous to the phosphotyrosine-binding domain (PTB) in the adaptor protein Shc. In Shc, this domain interacts with specific phosphotyrosine containing motifs on receptor tyrosine kinases and other signaling molecules. Residues N-terminal to the phosphotyrosine are also crucial for phosphopeptide binding to the Shc PTB domain. Several amino acid residues in Shc have been implicated by site-directed mutagenesis to be critical for Shc binding to receptor tyrosine kinases. We have generated homologous mutations in Numb to test whether, in vivo, these changes affect Numb function during Drosophila sensory organ development. Two independent amino acid changes that interfere with Shc binding to phosphotyrosine residues do not affect Numb activity in vivo. In contrast, a mutation shown to abrogate the ability of the Shc PTB domain to bind residues upstream of the phosphotyrosine virtually eliminates Numb function. Similar results were observed in vitro by examining the binding of the Numb PTB domain to proteins from Schneider S2 cells. Our data confirm the importance of the PTB domain for Numb function but strongly...Continue Reading

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Citations

Jun 4, 1999·Progress in Biophysics and Molecular Biology·Z Songyang
Aug 26, 1999·Trends in Endocrinology and Metabolism : TEM·B Margolis
Dec 28, 1999·Kidney International·B MargolisD Meyer
Mar 31, 2005·Molecular and Cellular Biology·Haiyan TangWeimin Zhong
Mar 2, 2006·Developmental Neuroscience·Petur H PetersenWeimin Zhong
Jul 23, 2014·Asian-Australasian Journal of Animal Sciences·Zhi-Juan YangSong-Jia Lai
May 17, 2011·Developmental Cell·Pengcheng ZhouRosalind A Segal
May 8, 2002·Nature Reviews. Molecular Cell Biology·Michael B Yaffe
May 24, 2017·The EMBO Journal·Jérémy SalléAllison J Bardin
Dec 13, 2003·The Journal of Biological Chemistry·Hanjuan QinShawn S-C Li

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