Cell regulation by tyrosine phosphorylation and ubiquitination
Jonathan A. Cooper
Member and Director of the Division of Basic Sciences, Fred Hutch; Co-Head of the Program in Cancer Basic Biology, UW/Fred Hutch Cancer Consortium
Fred Hutchinson Cancer Research Center, UW Biochemistry
May 14, 2015
Foege N130A, Wallace H. Coulter Seminar Room
Phosphorylation and ubiquitination are two common post-translational modifications that regulate protein activities and protein-protein interactions in the cell. There is extensive cross-talk: for example, phosphorylation can turn a protein into a substrate for a ubiquitin ligase, while ubiquitination can target a protein for degradation, rendering it unavailable for phosphorylation. We have been studying a family of ubiquitin ligases (the SOCS-CRL5 family) that ubiquitinates proteins only after they have been phosphorylated at tyrosine residues. These ubiquitin ligases thus counteract the effects of tyrosine phosphorylation. Since many oncoproteins are tyrosine kinases, the phosphotyrosine-specific ubiquitin ligases can act as tumor suppressors. I’ll discuss to systems where the SOCS-CRL5 family provide a critical brake on tyrosine kinase activity, regulating cell migration in vivo and in vitro. From an engineering perspective, it is interesting to think in terms of how inhibition of kinase signaling that is essentially irreversible, due to ubiquitination followed by degradation, can have distinct effects from reversible inhibition by dephosphorylation. Moreover, our results suggest that cell behavior can be regulated by “global” depletion of a signaling protein throughout the cell or by “local” depletion at a particular subcellular site. I’ll contrast global/analog and local/digital control.
Dr. Cooper graduated with highest honors from Cambridge University and investigated interferon signaling for his PhD from the University of Warwick. Following postdoctoral research at the NIH studying vaccinia virus molecular biology, he joined Tony Hunter at the Salk Institute, where he identified some of the first substrates for oncogenic tyrosine kinases. After joining the faculty at Fred Hutch, his lab showed that the cellular Src proto-oncoprotein is repressed by phosphorylation by another kinase, Csk, and was the first to identify a phosphorylation site that recruits a signaling protein to an activated growth factor receptor, providing key evidence for the hypothesis that phosphorylation-induced protein complexes relay signals inside the cell. They also showed that Ras activates Raf by direct binding. In 1995, postdoc Brian Howell identified Dab1, a homolog of a Drosophila neurodevelopmental gene that is expressed in developing mouse brain. His studies on a Dab1 helped elucidate a signaling pathway that regulates neuron migrations during mammalian brain development. Further study revealed the importance of negative feedback by ubiquitin-dependent proteolysis, catalyzed by SOCS-CRL5 ubiquitin ligase. Moving back into non-neural systems, they found that SOCS-CRL5 also regulates the migration and growth of fibroblasts and epithelial cells. Their present focus is to identify proteins that are phosphorylated by Src and ubiquitinated by SOCS-CRL5 and elucidate their roles in cell migration and proliferation. Dr. Cooper is presently a Member and Director of the Division of Basic Sciences at Fred Hutch and co-Head of the Program in Cancer Basic Biology of the UW/Fred Hutch Cancer Consortium. He serves on the editorial boards of MCB and eLife.