Welcome to the Cooper Lab

Regulation of cell and developmental biology by tyrosine phosphorylation and phosphotyrosine-directed ubiquitylation

Post-translational protein modifications, including phosphorylation and ubiquitinylation, are well known to regulate protein functions as cells respond to their environments. We have been studing the roles of protein phosphorylation, by protein-tyrosine kinases, and ubiquitylation, by phosphotyrosine-targeted ubiquitin ligases, in regulating various aspects of cell and developmental biology. Specifically, we have found that protein tyrosine-phosphorylation and ubiquitylation regulate cell proliferation, transformation and migration in normal and cancer cells. Current work in the lab uses the tools of molecular, cellular and developmental biology to understand the mechanisms involved.

Protein phosphorylation by protein kinases is generally reversed by protein phosphatases. In addition, however, some phosphoproteins are targeted for ubiquitinylation by phospho-specific ubiquitin ligases. Two families of ubiquitin ligases, the Cbl family and the Cullin5-RING ligases (CRL5s), target phosphotyrosine proteins for ubiquitinylation. Substrate-recognition (adaptor) components of CRL5, known as SOCS proteins, determine which phosphoproteins are ubiquitinated. SOCS protein expression is regulated, allowing complex temporal and spatial control of CRL5 specificity.

Ubiquitination by CRL5s generally leads to proteasomal destruction. Unlike dephosphorylation by protein phosphatases, proteasomal destruction is irreversible. Protein phosphatases set the steady state abundance of phosphoproteins, but phosphoprotein-specific ubiquitin ligases set the phosphoprotein half-life, and can set the time during which signaling occurs, creating a negative feedback loop. This has important implications for the spatiotemporal dynamics of intracellular signaling.

We are using two different systems to understand the roles of tyrosine kinases, ubiquitin ligases and other signaling molecules in regulating cell and developmental biology.

Time lapse movie of cortical neurons in slice culture. Neurons were labeled three days previously by in utero electroporation. Many cells express a red fluorescent nuclear marker and a subset expresses a green actin marker. Neurons that have finished migrating appear to move downwards because the top of the slice was fixed during the movie. Note the protrusive activity. (Susumu Antoku)