Daniel J. Donoghue
Professor of Chemistry/Biochemistry
Ph.D., Massachusetts Institute of Technology
"Fibroblast Growth Factor Receptors (FGFRs) 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 exclusively 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.
We were the first group to show the potential oncogenicity of FGFR4 in experiments that compared its transforming ability with FGFR1 and FGFR3, representing the first demonstration that activation of FGFR4, in addition to FGFR1 and FGFR3, can induce cellular transformation.
We have also detected sites of phosphorylation within the kinase insert domain (KID) of FGFR2. We are currently exploring whether these residues contribute to the activation of FGFR2 and lead to the recruitment of binding proteins to the KID. We are working towards identification of a novel mechanism of FGFR2 regulation beyond the kinase domain in which the KID also contributes to the activation of FGFR2, and perhaps, to the onset of breast cancers in which FGFR2 has been heavily implicated.
We are now concentrating our research efforts towards understanding the role of FGFR4 activation and its impact on downstream signaling in diseases such as prostate and breast carcinomas. In particular, we are investigating the role of FGFR4 and FGFR2 in the regulation of the Nuclear Factor kappaB (NFkappaB) inflammatory signaling pathway. We have already demonstrated a direct interaction between FGFR4 and IKKbeta, the major regulatory kinase of NFkappaB signaling.
Since our first observation of the oncogenic potential of FGFR4 more than a decade ago, occasional reports have shown the involvement of FGFR4 in diseases such as prostate and colon cancers. However, only one study has shown that FGFR4 leads to the metastasis of Rhabdomyosarcoma (RMS), a pediatric sarcoma that leads to the formation of tumors in head, neck, and trunk. We are therefore applying our knowledge of FGFR4 signaling to analyze its importance in RMS.
BMS Focus Areas:
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. 2014 PLoS One PONE-D-13-33878R1 (in press).
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:
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:
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.