We will determine the contributions of the four receptor tyrosine kinase (RTK) domains to the energetics of RTK lateral dimerization. The six receptors chosen for this study, ErbB1, ErbB2, ErbB3, FGFR1, FGFR2, and FGFR3, have been linked to human pathologies. The contributions of the different domains in these six RTKs to the dimerization free energies are currently unknown, mainly due to experimental challenges in the study of full-length RTKs, and membrane proteins in general. Here we will use a novel experimental approach, based on quantitative FRET, which yields dimerization thermodynamics in plasma membranes derived from mammalian cells. The work proposed here is the first step towards comprehensive characterization of the interplay between the different RTK domains in signaling. It will provide basic knowledge regarding the role of the different domains in the dimerization process, and thus aid in the development of highly specific therapeutics which can be used to treat cancers and growth disorders.

Public Health Relevance

RTK domains and RTK dimerization thermodynamics Narrative Many pathologies are believed to occur due to disregulation of ligand-independent RTK dimerization. Here we will gain insight into this process by determining the contributions of the four receptor tyrosine kinase (RTK) domains to the energetics of RTK dimerization. The proposed work will aid in the development of highly specific therapeutics that can be used to treat cancers and growth disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068619-09
Application #
8536822
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Chin, Jean
Project Start
2004-05-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2013
Total Cost
$308,700
Indirect Cost
$117,630
Name
Johns Hopkins University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sarabipour, Sarvenaz; King, Christopher; Hristova, Kalina (2014) Uninduced high-yield bacterial expression of fluorescent proteins. Anal Biochem 449:155-7
Placone, Jesse; He, Lijuan; Del Piccolo, Nuala et al. (2014) Strong dimerization of wild-type ErbB2/Neu transmembrane domain and the oncogenic Val664Glu mutant in mammalian plasma membranes. Biochim Biophys Acta 1838:2326-30
Bocharov, Eduard V; Lesovoy, Dmitry M; Goncharuk, Sergey A et al. (2013) Structure of FGFR3 transmembrane domain dimer: implications for signaling and human pathologies. Structure 21:2087-93
Sarabipour, Sarvenaz; Hristova, Kalina (2013) FGFR3 transmembrane domain interactions persist in the presence of its extracellular domain. Biophys J 105:165-71
Chen, Fenghao; Sarabipour, Sarvenaz; Hristova, Kalina (2013) Multiple consequences of a single amino acid pathogenic RTK mutation: the A391E mutation in FGFR3. PLoS One 8:e56521
Li, Edwin; Wimley, William C; Hristova, Kalina (2012) Transmembrane helix dimerization: beyond the search for sequence motifs. Biochim Biophys Acta 1818:183-93
He, Lijuan; Serrano, Christopher; Niphadkar, Nitish et al. (2012) Effect of the G375C and G346E achondroplasia mutations on FGFR3 activation. PLoS One 7:e34808
Wimley, William C; Hristova, Kalina (2011) Antimicrobial peptides: successes, challenges and unanswered questions. J Membr Biol 239:27-34
Hristova, Kalina; Wimley, William C (2011) A look at arginine in membranes. J Membr Biol 239:49-56
Chen, Fenghao; Degnin, Catherine; Laederich, Melanie et al. (2011) The A391E mutation enhances FGFR3 activation in the absence of ligand. Biochim Biophys Acta 1808:2045-50

Showing the most recent 10 out of 32 publications