Abstract/Details

System-level studies of receptor tyrosine kinase signaling networks


2009 2009

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Abstract (summary)

Receptor tyrosine kinases are transmembrane proteins that activate intracellular signaling pathways in response to extracellular ligands. Upon activation, receptor tyrosine kinases recruit proteins containing SH2 and PTB domains to sites oftyrosine phosphorylation on the receptors, which is the initial step in intracellular signaling. Despite the fact that RTKs induce diverse biological responses including proliferation, migration and differentiation, they often recruit similar sets of SH2- and PTB-containing proteins and activate many of the same signaling pathways. In order to assess how seemingly similar receptors induce distinct biological outcomes, a protein microarray platform was developed to assess the global recruitment of SH2- and PTB-containing proteins to receptor tyrosine kinases. These arrays consisted of purified SH2 and PTB domains printed in wells of a microtiter plate and were probed with a dilution series of fluorescently labeled phosphotyrosine-containing peptides. This format was used to generate quantitative interaction maps for the four ErbB [epidermal growth factor receptor (EGFR) family] receptors. To extend these studies to cellular events, six diverse receptor tyrosine kinases were expressed in a common cellular background, and the phosphorylation of intracellular proteins induced by each receptor was measured by immunoblotting. Each receptor induced a unique phosphorylation pattern based on intrinsic differences in signaling properties. Using global recruitment profiles for the six receptors determined with protein microarrays, it was found that the phosphorylation of upstream signaling proteins can be modeled as a linear function of recruitment events. Finally, as physiological concentrations of extracellular ligands vary, the pathway activation induced by a single receptor, EGFR, was assessed in response to diverse ligand concentrations. Low ligand concentrations were found to fully activate most canonical signaling proteins, while much higher ligand concentrations were required to activate a subset of proteins. The ligand concentrations needed to activate both sets of proteins implicate the involvement of high- and low-affinity EGFR in distinct pathways, and suggest, for the first time, a role for low-affinity receptors in autocrine and paracrine signaling

Indexing (details)


Subject
Cellular biology;
Biochemistry
Classification
0379: Cellular biology
0487: Biochemistry
Identifier / keyword
Pure sciences; Biological sciences; EGFR; Protein microarrays; Receptor tyrosine kinase; Signaling networks
Title
System-level studies of receptor tyrosine kinase signaling networks
Author
Krall, Jordan Asher
Number of pages
134
Publication year
2009
Degree date
2009
School code
0084
Source
DAI-B 70/07, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781109256642
Advisor
MacBeath, Gavin
University/institution
Harvard University
University location
United States -- Massachusetts
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3365317
ProQuest document ID
304892859
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304892859
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