Regulation of Notch Signaling by Src Kinase

Abstract

Notch signaling is a form of intercellular communication which plays pivotal roles at various stages in development and disease. The Notch receptor is a single‐pass transmembrane receptor which undergoes proteolytic processing upon binding with a ligand extending from an adjacent cell's membrane. This ligation and subsequent cleavage liberates the transcriptionally active intracellular domain of Notch from the full length receptor. The emancipated Notch intracellular domain undergoes nuclear translocation where it facilitates target gene transcription. Through this series of molecular events, cells can enact changes in a neighboring cell's gene expression patterns. It is now being revealed that Notch signaling has roles which extend beyond juxtacrine signal transduction. Work in our laboratory focuses on the mechanisms by which Notch signaling integrates cell‐cell stimuli with extracellular cues. In a recent publication from our laboratory, we reported that integrin signaling is capable coordinating the Notch pathway. Here, we reveal that the regulation of Notch by integrins is carried out by Src family kinases working downstream of integrins. This is achieved through the phosphorylation of tyrosine residues, within the Notch intracellular domain, by Src. While serine/threonine phosphorylation of the Notch receptor has been well characterized and is essential to important regulatory events, the tyrosine phosphorylation of the Notch receptor is a relatively unexplored area of research. We have identified four tyrosine residues within the intracellular domain of Notch1 that are phosphorylated by Src. In order to observe the functional consequences of Src induced phosphorylation of Notch1, mutagenesis was performed at these sites. We have found that phosphorylation at these residues has implications for Notch1 intracellular domain stability and transcriptional activity. In addition to this work, we have investigated a number of polyphenolic compounds which are capable of binding integrins and regulating the Notch pathway. We report on the Notch induced ramifications of cellular stimulation with resveratrol, and related polyphenols, that alter Notch target gene transcription. Having established these results, we turn our attention towards the importance of Notch‐Src interactions and polyphenolic regulation of Notch signaling as it pertains to vascular biology.Support or Funding InformationNIH 2R15GM102852‐02, NIH 2R15GM102852‐01This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.