Dissertation/Thesis Abstract

Integrin-cytokine crosstalk and the development of dominant-negative mutants as potential therapeutics
by Yu, Jessica, Ph.D., University of California, Davis, 2015, 131; 3723760
Abstract (Summary)

Integrins are required for cytokine/growth factor signaling (integrin-cytokine crosstalk). Crosstalk between integrins and cytokine receptors are an important signaling mechanism during normal development and pathological processes. In current models integrins recognize extracellular matrix (ECM) and cytokines bind to cytokine receptor tyrosine kinases and two separate signals merge inside the cells.

We propose that the direct binding of integrins to cytokines, and subsequent ternary complex formation are critically important in signaling functions in several cytokine. Consistently, the integrin-binding defective cytokine mutants (which are functionally defective and antagonistic) described above all bind to cytokine receptors at levels comparable to that of WT cytokines. This indicates that the binding of these cytokines to cytokine receptors is not sufficient for their signaling functions. We hypothesize that direct binding of integrins to cytokines and cell surface receptors is involved in the biological action of this cytokine.

I have identified two cytokines: vascular endothelial growth factor (VEGF) and interleukin 1 beta (IL1β), and three cell surface receptors: CD9, CD81, CD151, as new integrin ligands. The C-terminal domain of VEGF165 (C55), by binding to both the first IgG-like domain of KDR/VEGFR2 and integrin &agr;vβ3, becomes a potential antagonist for VEGF165-induced angiogenesis. The direct crosstalk between integrin and IL1β accounts for the cytokine activity and the antagonistic activity of interleukin 1 receptor antagonist. We also identified three tetraspanins, a family of cell surface receptors, CD9, CD81, and CD151 as a novel ligand for integrin &agr;vβ3 through the classical RGD domain.

We thus concluded that direct crosstalk between integrins and cytokine, between integrins and cell surface receptors as a general mechanism for the action of the cytokine, the cell surface receptors, and many more other biological molecules including several chemokines. We hope to utilize this direct crosstalk to generate integrin-binding-defective mutants to block the disease-related cytokine or cell surface receptor function for bench-to-bedside transition.

Indexing (document details)
Advisor: Takada, Yoshikazu
Commitee: Izumiya, Yoshihiro, Sweeney, Colleen A.
School: University of California, Davis
Department: Cell and Developmental Biology
School Location: United States -- California
Source: DAI-B 77/02(E), Dissertation Abstracts International
Subjects: Biochemistry, Immunology
Keywords: Biochemistry, Cancer biology, Cytokine, Immunology, Integrins
Publication Number: 3723760
ISBN: 9781339066899
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