Disease relevance of Pdgfrb

• Our data show that PDGFR signaling quantitatively regulates tumor grade and is required to sustain high-grade oligodendrogliomas [1].
• Inhibition of PDGFR phosphorylation and Src and Akt activity by GN963 leads to therapy of human pancreatic cancer growing orthotopically in nude mice [2].
• CONCLUSIONS: These results indicate that PDGFR-beta plays a significant role in formation of fibrous atherosclerotic lesions and that regulation of the signal transduction through PDGFR-beta could affect atherogenesis in mice [3].
• BACKGROUND: Inhibiting phosphorylation of platelet-derived growth factor receptor (PDGFR) by treatment with the PDGFR kinase inhibitor imatinib and the chemotherapeutic agent paclitaxel reduces the incidence and size of human prostate cancer bone lesions in nude mice [4].
• These models include an ex vivo measure of PDGFR-beta phosphorylation in glioblastoma tumors, a sponge model to measure inhibition of angiogenesis, and multiple models of tumor growth inhibition [5].

High impact information on Pdgfrb

• Complete loss of function of both ligands, therefore, phenocopied the loss of PDGFR-alpha function, suggesting that both PDGF-A and PDGF-C signal through PDGFR-alpha to regulate the development of craniofacial structures, the neural tube and mesodermal organs [6].
• However, targetted inactivation of the Pdgfb gene or the Pdgf receptor beta (Pdgfrb) gene, by homologous recombination, does not prevent the development of apparently normal large arteries and connective tissue [7].
• Pdgfrb inactivation did not affect cell contribution to non-muscle mesodermal lineages, including fibroblasts and endothelial cells [7].
• This study revealed that the participation of Pdgfrb(-/-) cells in all muscle lineages (smooth, cardiac, skeletal and pericyte) was reduced by eightfold compared with Pdgfrb(+/+) cells, and that participation of Pdgfrb(+/-) cells was reduced by twofold (eightfold for pericytes) [7].
• The Akt activation was also shown to depend on PDGFR beta tyrosines Y740 and Y751, which bind phosphatidylinositol 3-kinase (PI 3-kinase) upon phosphorylation [8].

Chemical compound and disease context of Pdgfrb

• Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were also suppressed by repeated intrathecal injection of either the PDGF alpha receptor (PDGFRalpha)/Fc chimera protein or the PDGFR-dependent tyrosine kinase inhibitor AG17 [(3,5-di-tert-butyl-4-hydroxybenzylidene)-malononitrile] [9].
• Inactivation of LRP1 in vascular SMCs of mice causes PDGFR overexpression and abnormal activation of PDGFR signaling, resulting in disruption of the elastic layer, SMC proliferation, aneurysm formation, and marked susceptibility to cholesterol-induced atherosclerosis [10].

Biological context of Pdgfrb

• The c-Abl nonreceptor tyrosine kinase is activated by growth factor signals such as the platelet-derived growth factor (PDGF) and functions downstream of the PDGF-beta receptor (PDGFR) to mediate biological processes such as membrane ruffling, mitogenesis, and chemotaxis [11].
• The findings suggest that Shb may play a crucial role during early ES cell differentiation to vascular structures by transducing VEGFR-2 and PDGFR-beta signals [12].
• However, the importance of individual PDGFR-beta signal transduction pathways in vivo is not known [13].
• A mutant PDGFR chimera that was not able to detectably associate with or activate Src was compromised in its ability to mediate tyrosine phosphorylation of receptor-associated signaling molecules and initiated a submaximal activation of Erk [14].
• This study demonstrates that hematopoietic PDGF-B or PDGFR beta expression is not required for hematopoiesis or integrity of the cardiovascular system [15].

Anatomical context of Pdgfrb

• Furthermore, mRNA overexpression of Pdgfrb encoding platelet derived growth factor receptor beta and Egfr encoding epidermal growth factor receptor is associated with the timing of the growth of the esophageal epithelium in the neonatal mice [16].
• Signal transduction by the platelet-derived growth-factor receptor beta (PDGFR-beta) tyrosine kinase is required for proper formation of vascular smooth muscle cells (VSMC) [13].
• Introduction of these PDGF-R beta-related cDNAs into two partially transformed, CSF-1-dependent monocyte cell lines resulted in autonomous growth and cell transformation [17].
• Hematopoietic chimeras reconstituted with PDGF-B(-/-), PDGFR beta(-/-), 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 [15].
• These findings argue that differences in alpha and beta PDGF receptor substrate specificity in NIH/3T3 fibroblasts correlate with greater transforming activity mediated by the beta PDGFR [18].

Associations of Pdgfrb with chemical compounds

• Treatment of cells with the histone deacetylase (HDAC) inhibitor, Trichostatin A, increases PDGFRB promoter activity through the CCAAT motif and counteracts the repression caused by p73alpha [19].
• Our results suggest that a complex interplay between PDGFR and S1P receptors determines their functions [20].
• Increase in PDGFR-alpha in the absence of estradiol suggests direct effects of FSH signaling [21].
• Because tumor cells and tumor-associated endothelial cells express activated PDGFR, the primary target for imatinib has been unclear [4].
• Src family kinases are required for integrin but not PDGFR signal transduction [22].

Physical interactions of Pdgfrb

• Using deletion mutagenesis we mapped the PDGF binding site in each PDGFR to the D2-D3 region [23].

Regulatory relationships of Pdgfrb

• PDGF-A chain homodimer PDGF AA activates alpha-PDGFR only, and its role for cell migration is still debatable [24].
• 1O2 treatment did not induce phosphorylation of platelet-derived growth factor receptor (PDGFR) or activate SH-PTP2, a substrate of growth factor receptors, suggesting that PDGFR was not activated [25].
• Together these results indicate that RGS5 exerts control over PDGFR-beta and GPCR-mediated signaling pathways active during fetal vascular maturation [26].
• We conclude that TGF-beta regulates PDGFR alpha in the mammary stroma via a c-Cbl-independent mechanism [27].
• In fact, either cytokine deprivation of IL-3-dependent Ba/F3 cells or exposure of TEL/PDGFRbeta-expressing cells to the specific inhibitor of the PDGFR tyrosine kinase, CGP53716, caused a strong decrease in NF-kappaB activity followed by extensive cell death [28].

Other interactions of Pdgfrb

• Moreover, c-Abl and Arg, in turn, phosphorylate the PDGFR [11].
• The results position Fbn2 between the D18Mit35 and Pdgfrb loci in the central region of mouse Chr 18 [29].
• A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling [6].
• In Ang-2 null mutants, alpha SMA, desmin, and PDGFR beta prominently immunolocalized in cortical peritubular locations [30].
• Some alpha SMA-positive cells were closely associated with CD31- and Tie-2-positive peritubular capillary endothelia, and some of the alpha SMA-positive cells expressed PDGFR beta, desmin, and neural/glial cell 2 (NG2), consistent with a pericyte-like identity [30].

Analytical, diagnostic and therapeutic context of Pdgfrb

• The identity of PDGF and PDGFR proteins were further confirmed by immunoblotting [31].
• SU14813 inhibited VEGFR-2, PDGFR-beta, and FLT3 phosphorylation in xenograft tumors in a dose- and time-dependent fashion [32].
• We performed immunohistochemistry in the embryonic cerebrum with antibodies against NG2, platelet-derived growth factor receptor-alpha (PDGFR-alpha) and leptin receptor (Ob-R) [33].
• The amounts of cell surface PDGFR protein diminish in parallel with the mRNA levels during differentiation, as shown by Western blotting and PDGF-binding assays [34].
• Northern blot analysis failed to detect PDGFR-beta mRNA in mutant cells [35].

References