Ubiquitination in Diverse Signaling and Cancers

Ubiquitination pathways are important posttranslational modifications involved in diverse biological processes.

It has been well established that ubiquitination serves as a key mode for orchestrating protein stability and degradation. However, recent studies from my group and others have revealed novel roles of ubiquitination in non-proteolytic functions. We have shown that K63-linked ubiquitination of Akt facilitates Akt membrane localization and subsequent activation in response to diverse growth factors (Science, 2009).

Interestingly, we found distinct growth factors utilize diverse E3 ligases to elicit Akt ubiquitnation for Akt activation (Cell, 2012). Importantly, the cancer-associated Akt mutant-Akt E17K, recently identified in a subset of human cancers, displays enhanced K63-linked ubiquitination of Akt, in turn contributing to Akt hyperactivation, suggesting a role for Akt ubiquitination in aberrant Akt activation and cancer development (Science, 2009; Cell, 2012). Thus, this novel posttranslational modification of Akt represents an exciting and novel avenue for cancer research that has advanced our current understanding of how Akt signaling activation is regulated.

In addition to study how ubiquitination regulates growth factor receptors/kinase signaling, we are also exploring the role of non-proteolytic ubiquitination in diverse molecular and biological processes including DNA damage signaling and repair, protein trafficking, and epigenetic and transcriptional regulation.

We believe such study will not only offer new insights for signaling control, but also lead to novel therapeutic targets for cancer.