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Expression of a transmembrane phosphotyrosine phosphatase inhibits cellular response to platelet-derived growth
R A Mooney1, G G Freund, B A Way
1Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, New York 14642.
Abstract:
Tyrosine phosphorylation is a mechanism of signal transduction shared by many growth factor receptors and oncogene products. Phosphotyrosine phosphatases (PTPases) potentially modulate or counter-regulate these signaling pathways. To test this hypothesis, the transmembrane PTPase CD45 (leukocyte common antigen) was expressed in the murine cell line C127. Hormone-dependent autophosphorylation of the platelet-derived growth factor (PDGF) and insulin-like growth factor-1 (IGF-1) receptors was markedly reduced in cells expressing the transmembrane PTPase. Tyrosine phosphorylation of other PDGF-dependent phosphoproteins (160, 140, and 55 kDa) and IGF-1-dependent phosphoproteins (145 kDa) was similarly decreased. Interestingly, the pattern of growth factor-independent tyrosine phosphorylations was comparable in cells expressing the PTPase and control cells. This suggests a selectivity or accessibility of the PTPase limited to a subset of cellular phosphotyrosyl proteins. The maximum mitogenic response to PDGF and IGF-1 in cells expressing the PTPase was decreased by 67 and 71%, respectively. These results demonstrate that a transmembrane PTPase can both affect the tyrosine phosphorylation state of growth factor receptors and modulate proximal and distal cellular responses to the growth factors.
Insights
Transmembrane phosphotyrosine phosphatases (PTPases), like CD45, reduce growth factor receptor tyrosine phosphorylation. This modulation impacts cellular responses to platelet-derived growth factor (PDGF) and insulin-like growth factor-1 (IGF-1).
Area of Science:
- Cellular signaling pathways
- Signal transduction mechanisms
- Protein tyrosine phosphorylation
Background:
- Tyrosine phosphorylation is crucial for signal transduction, mediated by growth factor receptors and oncogene products.
- Phosphotyrosine phosphatases (PTPases) are key regulators that can modulate these signaling cascades.
- The transmembrane PTPase CD45's role in regulating growth factor signaling pathways requires further investigation.
Purpose of the Study:
- To investigate the effect of the transmembrane PTPase CD45 on tyrosine phosphorylation of growth factor receptors.
- To determine how CD45 expression influences cellular responses to platelet-derived growth factor (PDGF) and insulin-like growth factor-1 (IGF-1).
- To assess the selectivity of CD45 in dephosphorylating cellular phosphotyrosyl proteins.
Main Methods:
- Expression of the transmembrane PTPase CD45 in the murine C127 cell line.
- Analysis of hormone-dependent autophosphorylation of PDGF and IGF-1 receptors.
- Quantification of tyrosine phosphorylation in specific PDGF- and IGF-1-dependent phosphoproteins.
- Assessment of growth factor-independent tyrosine phosphorylations.
- Measurement of the maximum mitogenic response to PDGF and IGF-1.
Main Results:
- CD45 expression markedly reduced autophosphorylation of PDGF and IGF-1 receptors.
- Tyrosine phosphorylation of multiple PDGF- and IGF-1-dependent phosphoproteins was decreased.
- Growth factor-independent tyrosine phosphorylations remained comparable between CD45-expressing and control cells.
- Maximum mitogenic responses to PDGF and IGF-1 were significantly reduced (67% and 71%, respectively).
Conclusions:
- Transmembrane PTPases, exemplified by CD45, can effectively decrease tyrosine phosphorylation of growth factor receptors.
- CD45 modulates both proximal signaling events and distal cellular responses to growth factors.
- The PTPase activity appears selective, targeting a subset of cellular phosphotyrosyl proteins.