Distinguished Professor of Chemistry and Biochemistry
Co-Director, NIH Training Grant

Office: Urey Hall 4130
Phone: 858-534-7146
Email: ddonoghue@ucsd.edu
Group: View group members

1989-1993

Recipient of American Cancer Society Faculty Research Award

1988-1994

Co-recipient of Lucille P. Markey Foundation Charitable Trust Funds

1983-1986

Searle Scholars Fellowship

1980-1982

Helen Hay Whitney Fellowship

Cancer research and treatment is currently undergoing a revolution whereby an individual cancer can be treated as a molecular disease rather than an organ-specific disease. Many different molecular therapies have been developed which can be used for “precision medicine” or “personalized therapy”. To be successful, these approaches require a detailed molecular understanding of the genetic alterations that are responsible for each individual cancer.

The major focus of our lab is understanding “driver genes” of human cancer using cell biological, biochemical, and mass spec techniques. Many of our projects examine Receptor Tyrosine Kinases (RTKs), important signaling molecules that have evolved to transduce extracellular signals across the cellular membrane to activate intracellular pathways. Unfortunately, these same receptors may become abnormally activated, either by somatic point mutations or chromosomal translocations, resulting in cancer. Our lab is relatively small, highly focused, and very interactive. This year we are actively recruiting new students to join the lab. Below are short descriptions of ongoing research projects.

1. The oncogenic fusion protein BCR-FGFR1 (Breakpoint Cluster Region Protein fused to Fibroblast Growth Factor Receptor 1). BCR-FGFR1 functions as a driver of stem cell leukemia and lymphoma. Our research has shown that BCR-FGFR1 relies on the cellular chaperone Hsp90 for cellular stability and survival. Furthermore, we have uncovered a network of salt-bridge interactions essential for dimerization and activation of BCR-FGFR1. We have yet to understand if all FGFR1 fusion proteins share a common method of activation and oncogenic growth, and if these fusion proteins are able to downregulate various methods of cellular apoptosis.

2. The oncogenic fusion protein FGFR2-PPHLN1 (Fibroblast Growth Factor Receptor 2 fused to Periphilin 1). Arising from the biliary tract, Intrahepatic cholangiocarcinoma (ICC) is the second most common form of liver cancer, and universally fatal. Chromosomal translocations involving FGFR2 have been frequently identified, creating oncogenic fusion proteins. We have extensively characterized the oncogenic fusion FGFR2-PPHLN1, identified in 16% of ICC patients. We are interested in the role of the coiled-coil domain provided by the partner gene and whether disruption of this domain would provide better therapeutic effects.

3. The oncogenic fusion protein FGFR3-TACC3 (Fibroblast Growth Factor Receptor 3 fused to Transforming Acidic Coiled-Coil Containing Protein 3). FGFR3-TACC3 is an oncogenic fusion protein identified in glioblastoma, an aggressive brain cancer. After dimerization via the dimerizing partner TACC3, the kinase domain of FGFR3 becomes constitutively activated, resulting in activation of downstream signaling pathways. Following treatment with tyrosine kinase inhibitors (TKIs), resistance often emerges through mutations of “gatekeeper residues”, resulting in the need for new therapeutic approaches. This highlights the importance of analyzing the dimerizing partner of FGFR3-TACC3 to identify potential new drug targets for improving therapeutic methods.

4. Oncogenic fusion proteins with NTRK receptors. Neurotrophic tropomyosin receptor kinase (NTRK) chromosomal gene rearrangements have recently emerged as targets for cancer therapy. These receptors promote the regulation of cell proliferation, differentiation, apoptosis, and survival of neurons in both the central and peripheral nervous systems. We are undertaking studies to examine the oncogenic fusion proteins EML4-NTRK3, SQSTM1-NTRK1, and SQSTM-NTRK2 , which are found in mesenchymal tumor types.

5. Ubiquitination as a regulatory modification involved in oncogenic mutations. Ubiquitination is a post translational protein modification where a small regulatory protein, Ubiquitin (Ub), is covalently added to the substrate protein. We found that the activating mutation K171E in the activation loop of IKKβ, found in patients with multiple myeloma, spleen marginal zone lymphoma and mantle cell lymphoma, leads to the regulatory ubiquitination of K147, required for oncogenic signaling. We are also investigating the regulatory ubiquitination of the V600E mutation of BRAF, a serine/threonine kinase which serves as an oncogenic driver in melanoma.

6. Studies of Prostate Cancer stem cells. We are also studying prostate cancer stem cells, resulting in the characterization of an immortalized human stem cell-like prostate cancer cell line named iPS87. Advanced prostate cancer is incurable and it has been proposed that prostate cancer stem cells are responsible for reoccurrence and metastasis. We have found that FGFR signaling plays an important role in promoting proliferation and cell survival of these cells.

Cellular Biochemistry
Biophysics

Signaling Network Activation by Receptor Tyrosine Kinases

Representative Oncogenic RTK Fusion Proteins

Mass Spec Identification of Phosphorylation Sites in BCR-FGFR1