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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 "Similar Products" section below.

 

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

 

 

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.

 

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References