PDGF signalling is required for gastrulation of Xenopus laevis

Development ◽  
1995 ◽  
Vol 121 (9) ◽  
pp. 3099-3110 ◽  
Author(s):  
P. Ataliotis ◽  
K. Symes ◽  
M.M. Chou ◽  
L. Ho ◽  
M. Mercola
Keyword(s):  
Growth Factor ◽  
Marginal Zone ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Convergent Extension ◽  
Mesodermal Cell ◽  
Point Mutant ◽  
Receptor Alpha

During Xenopus gastrulation, platelet-derived growth factor (PDGF) receptor-alpha is expressed in involuting marginal zone cells which migrate over ectodermal cells expressing PDGF-A. To investigate the role of PDGF signalling during this process, we have generated a novel point mutant of PDGF receptor-alpha analogous to the W37 mutation of c-kit. This molecule is a specific, potent, dominant inhibitor of PDGF signalling in vivo. Injection of RNA encoding this protein into Xenopus embryos prevents closure of the blastopore, leads to abnormal gastrulation and a loss of anterior structures. Convergent extension is not inhibited in these embryos, but rather, involuting mesodermal cells fail to adhere to the overlying ectoderm. PDGF may therefore be required for mesodermal cell-substratum interaction.

Platelet-derived growth factor (PDGF)-dependent association of phospholipase C-gamma with the PDGF receptor signaling complex

1990 ◽  
Vol 10 (5) ◽  
pp. 2359-2366
Author(s):  
D K Morrison ◽  
D R Kaplan ◽  
S G Rhee ◽  
L T Williams
Keyword(s):  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Serine Phosphorylation ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Wild Type ◽  
Receptor Proteins ◽  
Signaling Complex

We investigated the interaction of phospholipase C-gamma (PLC-gamma) with wild-type and mutant forms of the platelet-derived growth factor (PDGF) beta-receptor both in vivo and in vitro. After PDGF treatment of CHO cell lines expressing wild-type or either of two mutant (delta Ki and Y825F) PDGF receptors, PLC-gamma became tyrosine phosphorylated and associated with the receptor proteins. The receptor association and tyrosine phosphorylation of PLC-gamma correlated with the ability of these receptors to mediate ligand-induced phosphatidylinositol turnover. However, both the delta Ki and Y825F mutant receptors were deficient in transmitting mitogenic signals, suggesting that the PDGF-induced tyrosine phosphorylation and receptor association of PLC-gamma are not sufficient to account for the growth-stimulatory activity of PDGF. Wild-type and delta Ki mutant PDGF receptor proteins expressed with recombinant baculovirus vectors also associated in vitro with mammalian PLC-gamma. However, baculovirus-expressed c-fms, v-fms, c-src, and Raf-1 proteins failed to associate with PLC-gamma under similar conditions. Phosphatase treatment of the baculovirus-expressed PDGF receptor greatly decreased its association with PLC-gamma. This requirement for receptor phosphorylation was also observed in vivo, where PLC-gamma could not associate with a mutant PDGF receptor (K602A) defective in autophosphorylation. PLC-gamma also coimmunoprecipitated with two other putative receptor substrates, the serine-threonine kinase Raf-1 and the 85-kilodalton phosphatidylinositol-3' kinase, presumably through its association with the ligand-activated receptor. Furthermore, baculovirus-expressed Raf-1 phosphorylated purified PLC-gamma in vitro at sites which showed increased serine phosphorylation in vivo in response to PDGF. These results suggest that PDGF directly influences PLC activity by inducing the association of PLC-gamma with a receptor signaling complex, resulting in increased tyrosine and serine phosphorylation of PLC-gamma.

scholarly journals Structural Role of Extracellular Domain 1 of α-Platelet-derived Growth Factor (PDGF) Receptor for PDGF-AA and PDGF-BB Binding

1995 ◽  
Vol 270 (46) ◽  
pp. 27595-27600 ◽  
Author(s):  
Daruka Mahadevan ◽  
Jin-Chen Yu ◽  
Jose W. Saldanha ◽  
Narmada Thanki ◽  
Peter McPhie ◽  
...  
Keyword(s):  
Growth Factor ◽  
Extracellular Domain ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Structural Role

Mechanism of Action and In Vivo Role of Platelet-Derived Growth Factor

1999 ◽  
Vol 79 (4) ◽  
pp. 1283-1316 ◽  
Author(s):  
Carl-Henrik Heldin ◽  
Bengt Westermark
Keyword(s):  
Growth Factor ◽  
Protein Tyrosine Kinase ◽  
Growth Stimulation ◽  
Receptor Activation ◽  
Platelet Derived Growth Factor ◽  
Cellular Effects ◽  
Structural And Functional Properties ◽  
Stimulation Of

Platelet-derived growth factor (PDGF) is a major mitogen for connective tissue cells and certain other cell types. It is a dimeric molecule consisting of disulfide-bonded, structurally similar A- and B-polypeptide chains, which combine to homo- and heterodimers. The PDGF isoforms exert their cellular effects by binding to and activating two structurally related protein tyrosine kinase receptors, denoted the α-receptor and the β-receptor. Activation of PDGF receptors leads to stimulation of cell growth, but also to changes in cell shape and motility; PDGF induces reorganization of the actin filament system and stimulates chemotaxis, i.e., a directed cell movement toward a gradient of PDGF. In vivo, PDGF has important roles during the embryonic development as well as during wound healing. Moreover, overactivity of PDGF has been implicated in several pathological conditions. The sis oncogene of simian sarcoma virus (SSV) is related to the B-chain of PDGF, and SSV transformation involves autocrine stimulation by a PDGF-like molecule. Similarly, overproduction of PDGF may be involved in autocrine and paracrine growth stimulation of human tumors. Overactivity of PDGF has, in addition, been implicated in nonmalignant conditions characterized by an increased cell proliferation, such as atherosclerosis and fibrotic conditions. This review discusses structural and functional properties of PDGF and PDGF receptors, the mechanism whereby PDGF exerts its cellular effects, and the role of PDGF in normal and diseased tissues.

scholarly journals Characterization of the tyrosine phosphorylation of calpactin I (annexin II) induced by platelet-derived growth factor

1991 ◽  
Vol 278 (2) ◽  
pp. 447-452 ◽  
Author(s):  
R Brambilla ◽  
R Zippel ◽  
E Sturani ◽  
L Morello ◽  
A Peres ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Platelet Derived Growth Factor ◽  
Annexin Ii ◽  
Necessary Condition ◽  
Pdgf Receptor ◽  
Permeabilized Cells ◽  
Phosphorylated Proteins ◽  
3T3 Fibroblasts

Stimulation in vivo of Swiss 3T3 fibroblasts with platelet-derived growth factor (PDGF) in the presence of orthovanadate induces the tyrosine phosphorylation of a 39 kDa protein, identified as the phosphorylated slow-migrating form of calpactin I (annexin II) heavy chain, p36. In fact, in PDGF-stimulated cells, anti-(calpactin I) antibodies recognize a doublet of bands, p36 and p39, and the latter disappears upon treatment with phosphatase. In many regards phosphorylation of p39 differs from the rapid and transient phosphorylation of the PDGF receptor and of other substrates: (a) it has slower kinetics but is then stable for longer periods of time; (b) it occurs at 37 degrees C but not at 4 degrees C; and (c) whereas most of the tyrosine-phosphorylated proteins are associated with membrane-enriched preparations, membrane association of p39 only occurs in the presence of Ca2+. Moreover, calpactin I leaks out of permeabilized cells at 0.1 microM free Ca2+, whereas it remains associated with the cells at concentrations of Ca2+ greater than or equal to 1 microM. PDGF does not stimulate phosphoinositide turnover (and thus Ca2+ mobilization) at 4 degrees C; thus it can be suggested that the Ca(2+)-dependent translocation of the protein to membrane/cytoskeletal structures is a necessary condition for its phosphorylation. In addition, calpactin I may not be a direct substrate for the PDGF receptor kinase, but rather the substrate of another tyrosine kinase activated by the receptor.

scholarly journals Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis

2005 ◽  
Vol 201 (6) ◽  
pp. 925-935 ◽  
Author(s):  
Amir Abdollahi ◽  
Minglun Li ◽  
Gong Ping ◽  
Christian Plathow ◽  
Sophie Domhan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Kinase Inhibitors ◽  
Platelet Derived Growth Factor ◽  
Growth Factor Signaling ◽  
Pdgf Receptor ◽  
Pdgf Signaling ◽  
Radiation Induced

Pulmonary fibrosis is the consequence of a variety of diseases with no satisfying treatment option. Therapy-induced fibrosis also limits the efficacy of chemotherapy and radiotherapy in numerous cancers. Here, we studied the potential of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors (RTKIs) to attenuate radiation-induced pulmonary fibrosis. Thoraces of C57BL/6 mice were irradiated (20 Gy), and mice were treated with three distinct PDGF RTKIs (SU9518, SU11657, or Imatinib). Irradiation was found to induce severe lung fibrosis resulting in dramatically reduced mouse survival. Treatment with PDGF RTKIs markedly attenuated the development of pulmonary fibrosis in excellent correlation with clinical, histological, and computed tomography results. Importantly, RTKIs also prolonged the life span of irradiated mice. We found that radiation up-regulated expression of PDGF (A–D) isoforms leading to phosphorylation of PDGF receptor, which was strongly inhibited by RTKIs. Our findings suggest a pivotal role of PDGF signaling in the pathogenesis of pulmonary fibrosis and indicate that inhibition of fibrogenesis, rather than inflammation, is critical to antifibrotic treatment. This study points the way to a potential new approach for treating idiopathic or therapy-related forms of lung fibrosis.

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