PDGFR

Platelet-derived growth factor (PDGF) is a family of disulfide-bonded dimeric molecules of A-, B-, C- and D-polypeptide chains (PDGF-AA, -AB, -BB, -CC and -DD). PDGF isoforms stimulate proliferation, survival and motility of connective tissue cells, and certain other cell types.

PDGFs have important roles during the embryonal development to stimulate the differentiation and proliferation of specific mesenchymal cell types in different organs, such as smooth muscle cells and pericytes of blood vessels, mesangial cells in the kidney, alveolar myofibroblasts of the lung, and glial cells of the central nervous system. In the adult, PDGF is important for wound healing and for the regulation of the interstitial fluid pressure of tissues. Overactivity of PDGF is associated with malignancies, and other diseases characterized by excessive cell proliferation, including atherosclerosis and fibrotic conditions.

The cellular effects of PDGF are mediated by α- and β-tyrosine kinase receptors. Each receptor contains five extracellular Ig-like domains and an intracellular kinase domain which contains an inserted sequence of about 100 amino acid residues without similarity to kinases. The PDGF chains bind the receptors with different specificities. Thus, the α-receptor binds A-, B- and C-chains, whereas the β-receptor binds B- and D-chains. Ligand binding induces receptor dimerization; depending on the stimulating isoform, αα-homodimers, ββ-homodimers or αβ-heterodimers are formed. Within the dimers, the receptors are autophosphorylated in trans, which has two important functions: Autophosphorylation of a conserved tyrosine residue in the activation loop of the kinase domain causes activation of the kinase, and autophosphorylation of a number of tyrosine residues outside the kinase domain creates binding sites for downstream SH2 domain-containing molecules; the binding and activation of such molecules initiates a number of signaling pathways which leads to cell growth, survival and migration.

More than 10 families of SH2 domain proteins bind to the α- and β-receptors. They are of different kinds, i.e. molecules with associated enzymatic activities which are activated and/or attracted to the inner leaflet of the cell membrane by the receptors, members of the Stat family of transcription factors which after activation are translocated to the nucleus where they effect transcription of specific genes, and adaptor molecules which mediate interactions with other signaling components. Examples of enzymes activated by PDGF receptors are the tyrosine kinase Src, phospholipase C-γ (PLC-γ), phosphatidylinositol-3’-kinase (PI3K), GTPase activating protein (GAP) for Ras, and the tyrosine phosphatase SHP-2. Examples of adaptors include Shc, Nck, Grb2, Grb7 and Crk. Transient inhibition of tyrosine phosphatases through PI3K-dependent production of H₂O₂ delays dephosphorylation and enhances the signals.

The α- and β-receptors have overlapping but distinct signaling capacities, which are mainly dictated by which SH2-domain molecules they bind. Thus, both receptors stimulate cell growth, but whereas the β-receptor potently stimulates chemotaxis, the α-receptor inhibits chemotaxis in certain cell types. In vivo experiments in mice, in which the cytoplasmic domains between the α- and β-receptors were swapped, revealed that the β-receptor intracellular domain can fully substitute for the α-receptor’s. However, replacement of the β-receptor’s cytoplasmic domain with that of the α-receptor causes abnormalities in vascular smooth muscle cell development and function.

There are examples that overactivity of PDGF receptors through enhanced autocrine ligand stimulation contributes to malignancies, e.g. dermatofibrosarcoma protuberans, in which the PDGF B-chain gene is fused to a collagen gene leading to the production of a fusion protein which is processed to PDGF-BB. There are also examples of activation of PDGF receptors by mutation in certain tumor types. Thus, translocation of the genes for PDGF α- or β-receptors occur in hypereosinophilic syndrome and atypic chronic myeloic leukemias. In these cases, fusion proteins are formed between the kinase domains of the receptors and other molecules which cause constitutive dimerization and activation of the kinases. In a subfraction of gastrointestinal stromal tumors, the activation loop of the α-receptor is mutated, and in a subfraction of glioblastoma multiforme, the α-receptor gene is amplified. In each one of these cases the overactive receptor causes constitutive growth and survival signals which contribute to malignant transformation. Treatment of patients with certain of these diseases with selective PDGF receptor tyrosine kinase inhibitors, has given promising results.

The Table below contains accepted modulators and additional information. For a list of additional products, see the Materials section below.

Table 1

Family Members	PDGFR-α	PDGFR-β
Other Names		CD140b
Molecular Weight/ Structural Data	170 kDa; 1098 aa	190 kDa; 1106 aa
Isoforms	Not Known	Not Known
Species	All vertebrates	All vertebrates
Domain Organization	Transmembrane domain 5 extracellular Ig-like domains Intracellular split tyrosine kinase domain	Transmembrane domain 5 extracellular Ig-like domains Intracellular split tyrosine kinase domain
Phosphorylation Sites	Tyr572 Tyr574 Tyr720 Tyr731 Tyr742 Tyr754 Tyr762 Tyr768 Tyr849 Tyr988 Tyr1018	Tyr579 Tyr581 Tyr716 Tyr740 Tyr751 Tyr763 Tyr771 Tyr775 Tyr778 Tyr857 Tyr1009 Tyr1021
Tissue Distribution	Fibroblasts, smooth muscle cells, glial cells	Fibroblasts, smooth muscle cells, pericytes
Subcellular Localization	Plasma membrane	Plasma membrane
Binding Partners/ Associated Proteins	SH2BPSM1 SHP-2 Cbl PLC-γ Src family kinase Shc PI3K Crk	SHP-2 PTP1c RasGAP Cbl PI3K PLCγ Nck Shb Grb7 STAT Src family kinases Shc Grb2/Sos
Upstream Activators	PDGF-AAa -ABa -BBa -CCa	PDGF-BBa -DDa
Downstream Activation	PI3K PLC-γ Grb2/Sos SHP-2 Src family kinases Shc Crk	SHP-2 PTP1c RasGAP c-cbl p558 p85a PLCγ Nck Shb Grb7 STAT Src family kinases Shc Grb2/Sos
Activators	Not Known	Not Known
Selective Inhibitors	Imatinib (Glevec) AG1295 AG1296 AGL2043 SU11248 (PZ0012)	Imatinib (Glevec) AG1295 AG1296 AGL2043 SU11248 (PZ0012) CDP860 (monoclonal antibody)
Selective Activators	Not Known	Not Known
Physiological Function	Development of lungs, intestinal villi, hair follicles and glial cells during embryogenesis	Development of kidneys and blood vessels during embryogenesis Stimulation of wound healing Regulation of interstitial fluid pressure in tissues
Disease Relevance	Glioblastoma Hypereosinophilic syndrome Gastrointestinal stroma tumor Atypic chronic myeloic leukemia (CMML)	Dermatofibrosarcoma protuberans Monomyelocytic leukemia Atherosclerosis Restenosis Fibrotic conditions

Table 2

Family Members	Fms	Flt3	Kit
Other Names	C-fms CD115 Colony stimulating factor 1 receptor CSF-1R CSF1R	CD135 Fetal liver kinase 2 Flk-2 Flk2 Flt-3 Flt3 Fms-like tyrosine kinase type 3 Fms-related tyrosine kinase 3 Ly72	Mast/stem cell growth factor receptor Bs c-KIT c-Kit receptor tyrosine kinase CD117 Fdc Kit PBT Ssm Steel factor receptor Stem cell factor receptor
Molecular Weight/ Structural Data	107 kDa; 972 aa	112 kDa; 993 aa	109 kDa; 976 aa
Isoforms	Not Known	Not Known	Not Known
Species	Cat Human Mouse Rat	Human Mouse	Cow Dog Goat Chicken Cat Human Mouse Rat Drosophila Frog Zebrafish Pufferfish Horse
Domain Organization	Transmembrane domain 5 extracellular Ig-like domains Intracellular split tyrosine kinase domain	Transmembrane domain 5 extracellular Ig-like domains Intracellular split tyrosine kinase domain	Transmembrane domain 5 extracellular Ig-like domains Intracellular split tyrosine kinase domain
Phosphorylation Sites	Tyr708	Not Known	Tyr823 Ser559 Ser721 Ser746 Ser821
Tissue Distribution	Bone marrow cells Differentiated blood mononuclear cells	Bone marrow cells Dendritic cells	Fetal brain Term placenta Mast cells
Subcellular Localization	Plasma membrane	Plasma membrane	Plasma membrane
Binding Partners/ Associated Proteins	PI3K p85 Fmip HSC73 PSF Clathrin Shp2 Sos1 Shp1 SHIP Grb2 Cbl NonO SOCS1 Mg2+	Socs1 FIZ1	APS
Upstream Activators	CSF	FL	Stem cell factor (SCF)
Downstream Activation	PI3K	STAT5a Grb2/Sos	PI3K
Activators	Not Known	Not Known	Not Known
Selective Inhibitors	Not Known	Not Known	Imatinib (Glivec)
Selective Activators	Not Known	Not Known	Not Known
Physiological Function	Differentiation of macrophages	Differentiation and mobilization of dendritic cells	Required for normal hematopoiesis, melanogenesis and gametogenesis
Disease Relevance	Chronic myelomonocytic leukemia Type M4 acute myeloblastic leukemia	Acute myelogenous leukemia piebaldism Acute myelogenous	Gastrointestinal stromal tumor (GIST) Leukemia Human mast cell disease

Footnotes

a) Can form homodimers of the respective receptor types. In addition, all PDGF isoforms, except PDGF-AA, can form PDGFRa/PDGFRb heterodimers in cells expressing both receptor types.

Materials

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References

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