Photo of Daniel J. Donoghue

Daniel J. Donoghue

Provost, Sixth College; Professor, Chemistry & Biochemistry
Ph.D., Massachusetts Institute of Technology
Email: ddonoghue@ucsd.edu

Research Interests:

Fibroblast Growth Factor Receptors (FGFRs) and Nuclear Factor kappaB (NFkappaB) signaling in Human Cancer 

I have a long-standing interest in Receptor Tyrosine Kinases (RTKs), a passion which evolved from my graduate work at MIT with Phil Sharp, Bob Weinberg and David Baltimore, and from my postdoctoral work in Tony Hunter's lab at the Salk Institute.  During the past decade, my research interests have also included some non-RTK projects (e.g. cyclin B and cyclin-like proteins such as Spy1, co-discovered in our lab).

More recently, I decided to focus on the Fibroblast Growth Factor Receptor (FGFR) family of RTKs and their roles in oncogenic and inflammatory signaling pathways, exploiting proteomic and genomic approaches such as mass spec analysis of proteins, and microarray analysis of gene expression to identify novel regulatory phosphorylation sites, protein-protein interactions, and gene interaction networks.

My group has investigated the role of FGFR4 and FGFR2 in the regulation of the Nuclear Factor kappaB (NFkappaB) inflammatory signaling pathway. Signaling regulated by NFκB is important to many inflammatory and autoimmune diseases, cancer, and stress responses. The kinase that directly regulates the canonical NFκB transcriptional pathway, Inhibitor of κB kinase beta (IKKβ), undergoes activation by Ser phosphorylation in response to inflammatory signals. We have demonstrated a direct interaction between IKKβ and FGFR4 and FGFR2. Using titanium dioxide-based phosphopeptide enrichment (TiO2)-liquid chromatography (LC)-high mass accuracy tandem mass spectrometry (MS/MS), we analyzed IKKβ phosphorylation in human cells expressing IKKβ and FGFR2 and identified an abundant site of Tyr phosphorylation at Tyr169 within the Activation Loop of IKKβ. The phosphomimic at this site confers a level of kinase activation and NFκB nuclear localization exceeding the iconic mutant S177E/S181E, demonstrating that RTK-mediated Tyr phosphorylation of IKKβ has the potential to directly regulate NFκB transcriptional activation.

We are also extensively studying specific mutations of IKKβ that have been identified in Multiple Myeloma, Spleen Marginal Zone Lymphoma and Mantle Cell Lymphoma. Our current research shows that mutation at a specific residue leads to constitutive activation of IKKb and increased ubiquitination. Through a combination of mass spectroscopy and cell biological experiments we have identified a novel K63-linked ubiquitination site in IKKb. These results will have extensive ramifications for understanding inflammatory signaling and devising new therapeutics that target these pathways.

The occurrence of a chromosomal translocation can result in the formation of two genes fused together such that, when translated, a fusion protein results and is often oncogenic. FGFR fusion proteins are increasingly being detected in a variety of cancers. Particularly, a fusion protein of FGFR3 and transforming acidic coiled-coil containing 3(TACC3) has been identified in glioblastoma, bladder cancer, lung cancer, oral cancer, head and neck cancer, and gallbladder cancer. In this fusion, as with almost all FGFR fusion proteins, it is presumed the partner protein provides a dimerization domain, allowing the FGFR fusion to dimerize and constitutively activate. Our lab is currently exploring the nature of this activation and its oncogenic signaling.


Track(s)

MCB

BMS Focus Areas:

Cancer Biology

Bioinformatics

Selected Publications:

Selected Recent Publications
 
Salazar L, Kashiwada T, Krejci P, Meyer AN, Casale M, Hallowell M,
Wilcox WR, Donoghue DJ, and Thompson LM. Fibroblast Growth Factor
Receptor 3 Interacts with and Activates TGF beta- Kinase 1 Tyrosine
Phosphorylation and NFkappaB signaling in Multiple Myeloma and
Bladder Cancer.  PLoS One. 23 Jan 2014 DOI: 10.1371 / journal.pone.0086470. 
PMID: 24466111; PMCID: 3900522.
 
Manickam K, Donoghue DJ, Meyer AN, Snyder PJ, Prior TW. Suppression of severe
achondroplasia with developmental delay and acanthosis nigricans by the
p.Thr651Pro mutation. Am J Med Genet A. 2014 Jan;164(1):243-50.
doi:10.1002/ajmg.a.36236. PMID: 24352917.
 
Meyer AN, Drafahl KA, McAndrew CW, Gilda JE, Gallo LH, Haas M, Brill LM,
Donoghue DJ. Tyrosine Phosphorylation Allows Integration of Multiple Signaling
Inputs by IKKbeta. PLoS One. 2013 Dec 27;8(12):e84497. 
doi:10.1371/journal.pone.0084497. PMID: 24386391; PMCID: PMC3873999.
 
Fiones RR, Yeargin J, Lee M, Kaur AP, Cheng C, Sun P, Wu C,
Wang-Rodriguez J, Meyer AN, Baird SM, Donoghue DJ, Haas M. Early
Human Prostate Adenocarcinomas Harbor Androgen-Independent Cancer
Cells. 2013. PLoS ONE 8(9): e74438.  doi:10.1371/journal.pone.0074438.
PMID: 24086346  PMCID: PMC3783414
 
Locascio LE, Donoghue DJ. KIDs rule: regulatory phosphorylation of
RTKs.  Trends Biochem Sci. 2013 Feb;38(2):75-84. doi:
10.1016/j.tibs.2012.12.001.  Epub 2013 Jan 9. PubMed PMID: 23312584.
 
Fidalgo da Silva E, Ansari SB, Maimaiti J, Barnes EA, Kong-Beltran
M, Donoghue DJ, Porter LA. The tumor suppressor tuberin regulates
mitotic onset through the cellular localization of cyclin B1. Cell
Cycle. 2011 Sep 15;10(18):3129-39.  Epub 2011 Sep 15. PubMed PMID:
21900748.
 
Drafahl KA, McAndrew CW, Meyer AN, Haas M, Donoghue DJ. The receptor
tyrosine kinase FGFR4 negatively regulates NF-kappaB signaling.
PLoS One. 2010 Dec 22;5(12):e14412. doi: 10.1371/journal.pone.0014412.
PubMed PMID: 21203561; PubMed Central PMCID: PMC3008709.
 
Salazar L, Kashiwada T, Krejci P, Muchowski P, Donoghue D, Wilcox
WR, Thompson LM. A novel interaction between fibroblast growth
factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase: 
activation-dependent regulation of ERK by p85 in multiple myeloma
cells. Hum Mol Genet. 2009 Jun 1;18(11):1951-61. doi: 10.1093/hmg/ddp116.
Epub 2009 Mar 13. PubMed PMID: 19286672; PubMed Central PMCID: 
PMC2902846. 
 
Ahier A, Rondard P, Gouignard N, Khayath N, Huang S, Trolet J,
Donoghue DJ, Gauthier M, Pin JP, Dissous C. A new family of receptor
tyrosine kinases with a venus flytrap binding domain in insects and
other invertebrates activated by aminoacids. PLoS One. 2009 May
21;4(5):e5651. doi: 10.1371/journal.pone.0005651.  PubMed PMID: 
19461966; PubMed Central PMCID: PMC2680970. 
 
Meyer AN, McAndrew CW, Donoghue DJ. Nordihydroguaiaretic acid
inhibits an activated fibroblast growth factor receptor 3 mutant
and blocks downstream signaling in multiple myeloma cells. Cancer 
Res. 2008 Sep 15;68(18):7362-70. doi: 10.1158/0008-5472.CAN-08-0575.
PubMed PMID: 18794123; PubMed Central PMCID: PMC2745924.
 
Golipour A, Myers D, Seagroves T, Murphy D, Evan GI, Donoghue DJ,
Moorehead RA, Porter LA. The Spy1/RINGO family represents a novel
mechanism regulating mammary growth and tumorigenesis. Cancer Res.
2008 May 15;68(10):3591-600. doi: 10.1158/0008-5472.CAN-07-6453.
PubMed PMID: 18483240.
 

Web Page:

http:// http://cancertraining.ucsd.edu/