PDGFRB

Platelet-derived growth factor receptor beta precursor (EC 2.7.10.1) (PDGF-R-beta) (PDGFR-beta) (Beta platelet-derived growth factor receptor) (Beta-type platelet-derived growth factor receptor) (CD140 antigen-like family member B) (Platelet-derived growth factor receptor 1) (PDGFR-1) (CD140b antigen) [PDGFR] [PDGFR1]

Publications

Secretome of Senescent Adipose-Derived Mesenchymal Stem Cells Negatively Regulates Angiogenesis.

PubMed

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Nowadays, paracrine regulation is considered as a major tool of mesenchymal stem cell (MSC) involvement in tissue repair and renewal in adults. Aging results in alteration of tissue homeostasis including neovascularization. In this study, we examined the influence of replicative senescence on the angiogenic potential of adipose-derived MSCs (ASCs). Angiogenic activity of conditioned medium (CM) from senescent and "young" ASCs was evaluated in chorioallantoic membrane (CAM) assay in ovo using Japanese quail embryos. Also, the formation of capillary-like tubes by human umbilical vein endothelial cells (HUVECs) in 3D basement membrane matrix Matrigel and HUVEC migration capacity were analyzed. Multiplex, dot-blot and gene expression analysis were performed to characterize transcription and production of about 100 angiogenesis-associated proteins. The results point to decreased angiogenic potential of senescent ASC secretome in ovo. A number of angiogenesis-associated proteins demonstrated elevation in CM after long-term cultivation. Meanwhile, VEGF (key positive regulator of angiogenesis) did not change transcription level and concentration in CM. Increasing both pro- (FGF-2, uPA, IL-6, IL-8 etc.) and antiangiogenic (IL-4, IP-10, PF4, Activin A, DPPIV etc.) factors was observed. Some proangiogenic genes were downregulated ([i]IGF1, MMP1, TGFB3, PDGFRB, PGF[/i]). Senescence-associated secretory phenotype (SASP) modifications after long-term cultivation lead to attenuation of angiogenic potential of ASC.

MeSH Terms

• Adult
• Angiogenic Proteins
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Cellular Senescence
• Chorioallantoic Membrane
• Female
• Human Umbilical Vein Endothelial Cells
• Humans
• Mesenchymal Stem Cells
• Middle Aged
• Neovascularization, Physiologic
• Paracrine Communication

Keywords

• adipose-derived mesenchymal stem cells (ASCs)
• angiogenesis
• replicative senescence
• senescence-associated secretory phenotype (SASP)

A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome.

PubMed

Full text

Missense variants located to the "molecular brake" in the tyrosine kinase hinge region of platelet-derived growth factor receptor-β, encoded by PFGFRB, can cause Penttinen-type (Val665Ala) and Penttinen-like (Asn666His) premature ageing syndromes, as well as infantile myofibromatosis (Asn666Lys and Pro660Thr). We have found the same de novo PDGFRB c.1997A>G p.(Asn666Ser) variants in two patients with lipodystrophy, acro-osteolysis and severely reduced vision due to corneal neovascularisation, reminiscent of a severe form of Penttinen syndrome with more pronounced connective tissue destruction. In line with this phenotype, patient skin fibroblasts were prone to apoptosis. Both in patient fibroblasts and stably transduced HeLa and HEK293 cells, autophosphorylation of PDGFRβ was observed, as well as increased phosphorylation of downstream signalling proteins such as STAT1, PLCγ1, PTPN11/SHP2-Tyr580 and AKT. Phosphorylation of MAPK3 (ERK1) and PTPN11/SHP2-Tyr542 appeared unaffected. This suggests that this missense change not only weakens tyrosine kinase autoinhibition, but also influences substrate binding, as both PTPN11 tyrosines (Tyr542 and Tyr580) usually are phosphorylated upon PDGFR activation. Imatinib was a strong inhibitor of phosphorylation of all these targets, suggesting an option for precision medicine based treatment.

MeSH Terms

• Acro-Osteolysis
• Adult
• Aging
• Apoptosis
• Cockayne Syndrome
• Female
• Genetic Predisposition to Disease
• HeLa Cells
• Humans
• Imatinib Mesylate
• Limb Deformities, Congenital
• Male
• Mitogen-Activated Protein Kinase 3
• Mutation, Missense
• Myofibromatosis
• Phenotype
• Phosphorylation
• Progeria
• Protein Interaction Maps
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Protein-Tyrosine Kinases
• Receptor, Platelet-Derived Growth Factor beta
• Signal Transduction

Expansion of the phenotype of Kosaki overgrowth syndrome.

PubMed

Full text

Skeletal overgrowth is a characteristic of several genetic disorders that are linked to specific molecular signaling cascades. Recently, we established a novel overgrowth syndrome (Kosaki overgrowth syndrome, OMIM #616592) arising from a de novo mutation in PDGFRB, that is, c.1751C>G p.(Pro584Arg). Subsequently, other investigators provided in vitro molecular evidence that this specific mutation in the juxtamembrane domain of PDGFRB causes an overgrowth phenotype and is the first gain-of-function point mutation of PDGFRB to be reported in humans. Here, we report the identification of a mutation in PDGFRB, c.1696T>C p.(Trp566Arg), in two unrelated patients with skeletal overgrowth, further confirming the existence of PDGFRB-related overgrowth syndrome arising from mutations in the juxtamembrane domain of PDGFRB. A review of all four of these patients with an overgrowth phenotype and PDGFRB mutations revealed postnatal skeletal overgrowth, premature aging, cognitive impairment, neurodegeneration, and a prominent connective tissue component to this complex phenotype. From a functional standpoint, hypermorphic mutations in PDGFRB lead to Kosaki overgrowth syndrome, infantile myofibromatosis (OMIM #228550), and Penttinen syndrome (OMIM #601812), whereas hypomorphic mutations lead to idiopathic basal ganglia calcification (OMIM #615007). In conclusion, a specific class of mutations in PDGFRB causes a clinically recognizable syndromic form of skeletal overgrowth.

MeSH Terms

• Acro-Osteolysis
• Basal Ganglia Diseases
• Bone and Bones
• Calcinosis
• Female
• Humans
• Limb Deformities, Congenital
• Male
• Myofibromatosis
• Phenotype
• Point Mutation
• Progeria
• Receptor, Platelet-Derived Growth Factor beta
• Signal Transduction

Keywords

• Kosaki overgrowth syndrome
• PDGFRB
• premature aging
• skeletal overgrowth