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An analysis of the structure and function of protein tyrosine phosphatase ⍺ Harder, Kenneth W.
Abstract
The molecular basis for the control of cell growth, proliferation, and differentiation involves the coordinated activities of a diverse collection of molecules. Many, if not all, developmental processes are influenced by growth factors, extracellular matrix components, and/or adhesion molecules, which elicit changes in cytoskeletal organization, metabolism, and gene transcription. Signal transduction often involves the activation of tyrosine kinase activity associated with specific receptors. Receptor, or receptor-linked tyrosine kinases, then orchestrate the assembly of multimeric signaling complexes and regulate the activities of various downstream enzymes. Thus, tyrosine kinases form a critical link between the extracellular environment and the signal transduction machinery of the cytoplasm. The protein tyrosine phosphatases (PTPs), by dephosphorylating phosphotyrosine residues, play a critical, albeit less understood role in the regulation of tyrosine phosphorylation. A search for additional members of the PTP family, which now includes over 40 enzymes, led to the identification of PTP⍺, a widelyexpressed receptor-like PTP. In studies aimed at characterizing this PTP, we expressed PTP⍺ in both eukaryotic and bacterial cells. To assess the potential substrate specificity of these enzymes, select bacterially expressed PTPs were assayed with a group of synthetic phosphopeptide substrates using a modified colorimetric assay. These studies suggested that the substrate specificity of PTPs such as PTPβ may be influenced by the context of amino acids surrounding a given phosphotyrosine residue. Studies of the in vivo activity of PTP⍺, investigated by its overexpression in human epidermoid cells, revealed a role for PTP⍺ in the activation and/or dephosphorylation of specific Src family kinases. Moreover, PTP⍺ overexpression dramatically increased the cell-substratum adhesion of these cells and altered the tyrosine phosphorylation and associations of specific focal adhesion molecules, suggesting a role for this enzyme in cell-adhesion. Furthermore, an SH3 domain-binding motif was identified in the membrane-proximal region of PTP⍺, which like similar proline-rich regions in various retroviral oncoproteins and cytokine receptors, was able to bind specific SH3 domains in vitro.
Item Metadata
Title |
An analysis of the structure and function of protein tyrosine phosphatase ⍺
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
1996
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Description |
The molecular basis for the control of cell growth, proliferation, and
differentiation involves the coordinated activities of a diverse collection of molecules.
Many, if not all, developmental processes are influenced by growth factors, extracellular
matrix components, and/or adhesion molecules, which elicit changes in cytoskeletal
organization, metabolism, and gene transcription. Signal transduction often involves the
activation of tyrosine kinase activity associated with specific receptors. Receptor, or
receptor-linked tyrosine kinases, then orchestrate the assembly of multimeric signaling
complexes and regulate the activities of various downstream enzymes. Thus, tyrosine
kinases form a critical link between the extracellular environment and the signal
transduction machinery of the cytoplasm. The protein tyrosine phosphatases (PTPs), by
dephosphorylating phosphotyrosine residues, play a critical, albeit less understood role in
the regulation of tyrosine phosphorylation. A search for additional members of the PTP
family, which now includes over 40 enzymes, led to the identification of PTP⍺, a widelyexpressed
receptor-like PTP. In studies aimed at characterizing this PTP, we expressed
PTP⍺ in both eukaryotic and bacterial cells. To assess the potential substrate specificity
of these enzymes, select bacterially expressed PTPs were assayed with a group of
synthetic phosphopeptide substrates using a modified colorimetric assay. These studies
suggested that the substrate specificity of PTPs such as PTPβ may be influenced by the
context of amino acids surrounding a given phosphotyrosine residue. Studies of the in
vivo activity of PTP⍺, investigated by its overexpression in human epidermoid cells,
revealed a role for PTP⍺ in the activation and/or dephosphorylation of specific Src family
kinases. Moreover, PTP⍺ overexpression dramatically increased the cell-substratum
adhesion of these cells and altered the tyrosine phosphorylation and associations of
specific focal adhesion molecules, suggesting a role for this enzyme in cell-adhesion.
Furthermore, an SH3 domain-binding motif was identified in the membrane-proximal region of PTP⍺, which like similar proline-rich regions in various retroviral oncoproteins
and cytokine receptors, was able to bind specific SH3 domains in vitro.
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Extent |
21588155 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-03-16
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0087827
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
1996-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
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Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.