SH2/PTB Domains

Intracellular signaling networks that involve protein tyrosine kinases are critical in the control of most cellular processes, including growth, adhesion, migration, differentiation, and apoptosis. Misregulation of these networks results in a variety of human diseases, including cancer, diabetes, and immune deficiency. Many of the proteins that participate in these networks contain Src homology 2 (SH2) and Phosphotyrosine Binding (PTB) domains, which recognize proteins that have been phosphorylated on tyrosine residues in a sequence-specific fashion. These domains help interpret extracellular signals by targeting their host proteins to the appropriate subcellular location, by directing the assembly of multiprotein complexes, or by modulating the enzymatic activity of their host proteins. Although SH2 and PTB domains have been studied extensively over the past two decades, most investigations have focused on one or a few molecules of interest. Thus, while traditional methods have yielded abundant information about individual domains, they have been less successful at providing us with an integrated understanding of the biological systems that they regulate. We are investigating the molecular recognition properties of every SH2 and PTB domain encoded in the human genome with respect to physiologically relevant targets in a quantitative fashion using protein microarray technology. We are also investigating the physiological relevance of the biophysical interactions that we measure on the arrays using traditional biochemical tools, as well as tandem mass spectrometry. These cell-based efforts are currently focused primarily on the ErbB family of receptor tyrosine kinases, which plays an important role in mediating cell-cell interactions during organogenesis and in adulthood. Overall, these studies are designed to shed light on how signaling proteins are integrated into complex networks and how we can intervene most effectively when these networks go awry.

(A) SH2 domain from Src. (B) PTB domain from Irs-1.