Substrate specificity of receptor tyrosine kinases is critical for selective signaling

Pineda, Maria L (September 2012) Substrate specificity of receptor tyrosine kinases is critical for selective signaling. PhD thesis, Cold Spring Harbor Laboratory.

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Abstract

The completion of the human genome project has marked a new beginning in biomedical sciences. As human cancer is a genetic disease, the field of oncology has been one of the first to be impacted by this historic revolution. High-throughput mutational profiling of tumors has provided an unprecedented amount of information on genetic changes leading to cancer and has already revolutionized the way lung cancers are classified and treated. Fundamental for successfully translating the information uncovered by these genetic studies into the clinic is the molecular and functional characterization of the identified genetic lesions. As part of these efforts, the goal of my thesis studies was to gain an understanding of how genetic lesions affecting receptor tyrosine kinases (RTKs) contribute to treatment response and survival differences observed in lung tumors. Phosphorylation of tyrosine residues in proteins was first described in 1979 as an activity of a viral transforming gene product. Soon afterwards RTKs were recognized to play a role in transducing growth factor signals across the plasma membrane. Over the past 50 years, the importance of RTKs has been demonstrated in multiple studies, and increasing amounts of data have implicated the deregulation and malfunction of these signaling proteins in a variety of diseases including lung cancer. Although highly similar in structure and regulation, different RTKs exert distinct biological functions. The ability of RTKs to function within common pathways, yet induce diverse phenotypic responses, has largely been attributed to: 1) differences in cellular context, as signaling proteins are differentially expressed in distinct cell types; 2) the strength and temporal properties of signaling; and 3) differences in binding sites for effector molecules. In addition to these mechanisms, we discovered that intrinsic differences in RTK substrate specificity could also play a role in modulating functional differences among RTKs. In particular, we found the SOCS3 residue Y165 to be differentially phosphorylated by certain RTKs such as the platelet derived growth factor receptor (PDGFR) and the epidermal growth factor receptor (EGFR). The increased phosphorylation leads to ubiquitination and proteasome-dependent degradation of SOCS3. As SOCS3 is one of the major negative regulators of IL-6 mediated signaling, degradation of SOCS3 by PDGFR-mediated phosphorylation results in potentiation of IL-6 signaling, and phenotypically in the acquisition of mesenchymal-like features and increased metastatic potential as well as erlotinib resistance.

Item Type: Thesis (PhD)
Uncontrolled Keywords: RTK's Receptor Tyrosine Kinases Substrate Specificity Peptide Screen
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
diseases & disorders > cancer > cancer types > lung cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein expression > phosphorylation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Sordella lab
Watson School > Theses
Depositing User: Matt Covey
Date: 18 September 2012
Date Deposited: 29 Nov 2012 20:28
Last Modified: 21 Sep 2016 18:47
URI: http://repository.cshl.edu/id/eprint/26272

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