Integrins Enhance Platelet-derived Growth Factor (PDGF)-dependent Responses by Altering the Signal Relay Enzymes That Are Recruited to the PDGF β Receptor

Abstract Platelet-derived growth factor (PDGF)-B and PDGF β-receptor (PDGFRβ) deficiency in mice is embryonic lethal and results in cardiovascular, renal, placental, and hematologic disorders. The hematologic disorders are described, and a correlation with hepatic hypocellularity is demonstrated. To explore possible causes, the colony-forming activity of fetal liver cells in vitro was assessed, and hematopoietic chimeras were demonstrated by the transplantation of mutant fetal liver cells into lethally irradiated recipients. It was found that mutant colony formation is equivalent to that of wild-type controls. Hematopoietic chimeras reconstituted with PDGF-B−/−, PDGFRβ−/−, or wild-type fetal liver cells show complete engraftment (greater than 98%) with donor granulocytes, monocytes, B cells, and T cells and display none of the cardiovascular or hematologic abnormalities seen in mutants. In mouse embryos, PDGF-B is expressed by vascular endothelial cells and megakaryocytes. After birth, expression is seen in macrophages and neurons. This study demonstrates that hematopoietic PDGF-B or PDGFRβ expression is not required for hematopoiesis or integrity of the cardiovascular system. It is argued that metabolic stress arising from mutant defects in the placenta, heart, or blood vessels may lead to impaired liver growth and decreased production of blood cells. The chimera models in this study will serve as valuable tools to test the role of PDGF in inflammatory and immune responses.

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Loss of T-Cell Protein Tyrosine Phosphatase Induces Recycling of the Platelet-derived Growth Factor (PDGF) β-Receptor but Not the PDGF α-Receptor

Molecular Biology of the Cell ◽

10.1091/mbc.e06-04-0306 ◽

2006 ◽

Vol 17 (11) ◽

pp. 4846-4855 ◽

Cited By ~ 35

Author(s):

Susann Karlsson ◽

Katarzyna Kowanetz ◽

Åsa Sandin ◽

Camilla Persson ◽

Arne Östman ◽

...

Keyword(s):

T Cell ◽

Growth Factor ◽

Cell Surface ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Dominant Negative ◽

Platelet Derived Growth Factor ◽

Cell Protein ◽

Protein Tyrosine ◽

Β Receptor

We have previously shown that the T-cell protein tyrosine phosphatase (TC-PTP) dephosphorylates the platelet-derived growth factor (PDGF) β-receptor. Here, we show that the increased PDGF β-receptor phosphorylation in TC-PTP knockout (ko) mouse embryonic fibroblasts (MEFs) occurs primarily on the cell surface. The increased phosphorylation is accompanied by a TC-PTP–dependent, monensin-sensitive delay in clearance of cell surface PDGF β-receptors and delayed receptor degradation, suggesting PDGF β-receptor recycling. Recycled receptors could also be directly detected on the cell surface of TC-PTP ko MEFs. The effect of TC-PTP depletion was specific for the PDGF β-receptor, because PDGF α-receptor homodimers were cleared from the cell surface at the same rate in TC-PTP ko MEFs as in wild-type MEFs. Interestingly, PDGF αβ-receptor heterodimers were recycling. Analysis by confocal microscopy revealed that, in TC-PTP ko MEFs, activated PDGF β-receptors colocalized with Rab4a, a marker for rapid recycling. In accordance with this, transient expression of a dominant-negative Rab4a construct increased the rate of clearance of cell surface receptors on TC-PTP ko MEFs. Thus, loss of TC-PTP specifically redirects the PDGF β-receptor toward rapid recycling, which is the first evidence of differential trafficking of PDGF receptor family members.

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Tethering of the Platelet-derived Growth Factor β Receptor to G-protein-coupled Receptors

Journal of Biological Chemistry ◽

10.1074/jbc.m102771200 ◽

2001 ◽

Vol 276 (30) ◽

pp. 28578-28585 ◽

Cited By ~ 124

Author(s):

Forbes Alderton ◽

Soma Rakhit ◽

Kok Choi Kong ◽

Timothy Palmer ◽

Balwinder Sambi ◽

...

Keyword(s):

Growth Factor ◽

G Protein ◽

G Protein Coupled Receptors ◽

Platelet Derived Growth Factor ◽

Β Receptor ◽

G Protein Coupled

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Productive Interaction between Transmembrane Mutants of the Bovine Papillomavirus E5 Protein and the Platelet-Derived Growth Factor β Receptor

Journal of Virology ◽

10.1128/jvi.79.3.1924-1929.2005 ◽

2005 ◽

Vol 79 (3) ◽

pp. 1924-1929 ◽

Cited By ~ 9

Author(s):

Char-Chang Lai ◽

Anne P. B. Edwards ◽

Daniel DiMaio

Keyword(s):

Amino Acid ◽

Growth Factor ◽

Transmembrane Protein ◽

Platelet Derived Growth Factor ◽

Bovine Papillomavirus ◽

Transmembrane Region ◽

E5 Protein ◽

Β Receptor ◽

Membrane Spanning ◽

Lines Of Evidence

ABSTRACT The bovine papillomavirus E5 protein is a 44-amino-acid transmembrane protein that transforms cells by binding to the transmembrane region of the cellular platelet-derived growth factor (PDGF) β receptor, resulting in sustained receptor signaling. However, there are published reports that certain mutants with amino acid substitutions in the membrane-spanning segment of the E5 protein transform cells without activating the PDGF β receptor. We re-examined several of these transmembrane mutants, and here we present five lines of evidence that these mutants do in fact activate the PDGF β receptor, resulting in cellular signaling and transformation.

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