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 have been linked recently to genetic diseases characterized by connective tissue wasting (Penttinen syndrome) or overgrowth (Kosaki overgrowth syndrome), but it is unclear whether 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 mice and test the hypothesis that signal transducer and activator of transcription 1 (STAT1) mediates this phenotype. We show that mice with knockout ( ) are rescued from autoinflammation and have improved life span compared with mice. Furthermore, PDGFRβ-STAT1 signaling suppresses PDGFRβ itself. Thus, fibroblasts exhibit increased PDGFRβ signaling, and mice develop progressive overgrowth, a distinct phenotype from the wasting seen in mice. Deletion of interferon receptors ( or ) does not rescue wasting in 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.

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

“…3 and S1). STAT1 has recently been found necessary for the severe autoinflammation and wasting seen in mice with an activating PDGFRB variant (Asp849Val) [28]. PDGFRB activation on a STAT1 negative KO-mouse background was associated with overgrowth and prolonged life span, while the presence of STAT1 caused autoinflammation and wasting.…”

“…Of note, this apoptotic tendency coexisted with findings suggesting stimulation of tissue growth, like the patients' upper normal or tall statures (in childhood on the 75th and 97th centiles), the congenital haemangiomas and the corneal neovascularisation. It is well known that increased connective tissue growth can be caused by increased PDGFRβ signalling [4,28], and there are also previous indications that PDGFRβ overstimulation may cause apoptosis [29,30].…”

Latest advances in STAT signaling and function in adipocytes

“…STAT1 knockout mice that overexpress PDGFRß have recently been used to understand the biological relevance of PDGFRß-STAT1 signaling in adipocytes. In the absence of STAT1, mice overexpressing PDGFRß had no obvious defects, while mice expressing STAT1 and ectopically expressing PDGFRß were underweight and had increased mortality rates, accompanied by increased STAT1 activation and inflammation in adipose tissue [69]. Interestingly, these studies identified PDGFRß activation of STAT1 as a modulator of fibrosis in adipose tissue [69].…”

“…In adipocytes, many proinflammatory cytokines, such as IFNα and γ, can activate STAT1 [66]. Platelet-derived growth factor receptors (PDGFRs) has also been reported to activate STAT1 [67], and enhanced PDGFRß signaling is commonly associated with excessive cell proliferation, tissue wasting, and various genetic diseases [68,69]. STAT1 knockout mice that overexpress PDGFRß have recently been used to understand the biological relevance of PDGFRß-STAT1 signaling in adipocytes.…”

Recurrent, Activating Variants in the Receptor Tyrosine Kinase DDR2 Cause Warburg-Cinotti Syndrome

“…The latter is an important modifier in the overgrowth and tissue wasting seen in individuals with PDGFRB [MIM: 173410] gain-of-function variants. 9 The following proteins were assessed with appropriate antibodies, all obtained from Cell Signaling Technology at recommended dilutions (see Supplemental Methods for details): phospho-Tyr542-PTPN11(SHP-2), phospho-Tyr580-PTPN11(SHP-2), PTPN11(SHP-2), phospho-Ser473-AKT, AKT, phospho-Thr202/Tyr204-MAP-K3(ERK1), MAPK3(ERK1), phospho-Tyr416-SRC, Tyr416-SRC, phospho-Tyr527-SRC, Tyr527-SRC, SRC, and phospho-Tyr70-STAT1. We did not detect increased phosphorylation of any of these proteins (Figures S7-S21).…”