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STAT1 modulates tissue wasting or overgrowth downstream from PDGFRβ.

ABSTRACT: Platelet-derived growth factor (PDGF) acts through two conserved receptor tyrosine kinases: PDGFRα and PDGFRβ. Gain-of-function mutations in human PDGFRB have been linked recently to genetic diseases characterized by connective tissue wasting (Penttinen syndrome) or overgrowth (Kosaki overgrowth syndrome), but it is unclear whether PDGFRB mutations alone are responsible. Mice with constitutive PDGFRβ signaling caused by a kinase domain mutation (D849V) develop lethal autoinflammation. Here we used a genetic approach to investigate the mechanism of autoinflammation in Pdgfrb^+/D849V mice and test the hypothesis that signal transducer and activator of transcription 1 (STAT1) mediates this phenotype. We show that Pdgfrb^+/D849V mice with Stat1 knockout (Stat1^-/-Pdgfrb^+/D849V ) are rescued from autoinflammation and have improved life span compared with Stat1^+/-Pdgfrb^+/D849V mice. Furthermore, PDGFRβ-STAT1 signaling suppresses PDGFRβ itself. Thus, Stat1^-/-Pdgfrb^+/D849V fibroblasts exhibit increased PDGFRβ signaling, and mice develop progressive overgrowth, a distinct phenotype from the wasting seen in Stat1^+/-Pdgfrb^+/D849V mice. Deletion of interferon receptors (Ifnar1 or Ifngr1) does not rescue wasting in Pdgfrb^+/D849V mice, indicating that interferons are not required for autoinflammation. These results provide functional evidence that elevated PDGFRβ signaling causes tissue wasting or overgrowth reminiscent of human genetic syndromes and that the STAT1 pathway is a crucial modulator of this phenotypic spectrum.

SUBMITTER: He C

PROVIDER: S-EPMC5647937 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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STAT1 modulates tissue wasting or overgrowth downstream from PDGFRβ.

He Chaoyong C Medley Shayna C SC Kim Jang J Sun Chengyi C Kwon Hae Ryong HR Sakashita Hiromi H Pincu Yair Y Yao Longbiao L Eppard Danielle D Dai Bojie B Berry William L WL Griffin Timothy M TM Olson Lorin E LE

Genes & development 20170801 16

Platelet-derived growth factor (PDGF) acts through two conserved receptor tyrosine kinases: PDGFRα and PDGFRβ. Gain-of-function mutations in human <i>PDGFRB</i> have been linked recently to genetic diseases characterized by connective tissue wasting (Penttinen syndrome) or overgrowth (Kosaki overgrowth syndrome), but it is unclear whether <i>PDGFRB</i> mutations alone are responsible. Mice with constitutive PDGFRβ signaling caused by a kinase domain mutation (D849V) develop lethal autoinflammati ...[more]

PMID: 28924035

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Project description:BackgroundProtein tyrosine phosphatase 1B (PTP1B) is a protein tyrosine phosphatase and modulates platelet-derived growth factor (PDGF)/platelet-derived growth factor receptor (PDGFR) signaling in vascular smooth muscle cells (VSMCs) via endocytosis. However, the related molecular pathways that participated in the interaction of endo-lysosome and the trafficking of PDGFR are largely unknown. This study aims to determine the subcellular regulating mechanism of PTP1B to the endo-lysosome degradation of PDGFR in atherosclerotic carotid plaques, thereby offering a potential therapeutic target for the stabilization of carotid plaques.MethodsThe immunohistochemical staining technique was employed to assess the expression levels of both PDGFR-β and Caspase 3 in stable and vulnerable carotid plaques. Tunnel staining was utilized to quantify the apoptosis of carotid plaques. Live-cell imaging was employed to observe endocytic motility, while cell apoptosis was evaluated through Propidium Iodide staining. In an in vivo experiment, ApoE-/- mice were administered a PTP1B inhibitor to investigate the impact of PTP1B on atherosclerosis.ResultsThe heightened expression of PDGFR-β correlates with apoptosis in patients with vulnerable carotid plaques. At the subcellular level of VSMCs, PDGFR-β plays a pivotal role in sustaining a balanced endocytosis system motility, regulated by the expression of Rab5, a key regulator of endocytic motility. And PTP1B modulates PDGFR-β signaling via Rab5-mediated endocytosis. Additionally, disrupted endocytic motility influences the interplay between endosomes and lysosomes, which is crucial for controlling PDGFR-β trafficking. Elevated PTP1B expression induces cellular apoptosis and impedes migration and proliferation of carotid VSMCs. Ultimately, mice with PTP1B deficiency exhibit a reduction in atherosclerosis.ConclusionOur results illustrate that PTP1B induces disruption in endocytosis and apoptosis of VSMCs through the Rab5-PDGFRβ pathway, suggesting a potential association with the heightened vulnerability of carotid plaques.

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STAT1 modulates tissue wasting or overgrowth downstream from PDGFRβ.

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STAT1 modulates tissue wasting or overgrowth downstream from PDGFRβ.

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