RTK signaling requires C3ar1/C5ar1 and IL-6R joint signaling to repress dominant PTEN, SOCS1/3 and PHLPP restraint

FASEB J. 2020 Feb;34(2):2105-2125. doi: 10.1096/fj.201900677R. Epub 2019 Dec 13.

Abstract

How receptor tyrosine kinase (RTK) growth signaling is controlled physiologically is incompletely understood. We have previously provided evidence that the survival and mitotic activities of vascular endothelial cell growth factor receptor-2 (VEGFR2) signaling are dependent on C3a/C5a receptor (C3ar1/C5ar1) and IL-6 receptor (IL-6R)-gp130 joint signaling in a physically interactive platform. Herein, we document that the platelet derived and epidermal growth factor receptors (PDGFR and EGFR) are regulated by the same interconnection and clarify the mechanism underlying the dependence. We show that the joint signaling is required to overcome dominant restraint on RTK function by the combined repression of tonically activated PHLPP, SOCS1/SOCS3, and CK2/Fyn dependent PTEN. Signaling studies showed that augmented PI-3Kɣ activation is the process that overcomes the multilevel growth restraint. Live-cell flow cytometry and single-particle tracking indicated that blockade of C3ar1/C5ar1 or IL-6R signaling suppresses RTK growth factor binding and RTK complex formation. C3ar1/C5ar1 blockade abrogated growth signaling of four additional RTKs. Active relief of dominant growth repression via joint C3ar1/C5ar1 and IL-6R joint signaling thus enables RTK mitotic/survival signaling.

Keywords: IL-6 receptor; VEGFR2 signaling; local complement.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Genes, Dominant
  • Mice
  • Mice, Knockout
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Receptor, Anaphylatoxin C5a / genetics
  • Receptor, Anaphylatoxin C5a / metabolism*
  • Receptors, Complement / genetics
  • Receptors, Complement / metabolism*
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / metabolism*
  • Signal Transduction*
  • Suppressor of Cytokine Signaling 1 Protein / genetics
  • Suppressor of Cytokine Signaling 1 Protein / metabolism*
  • Suppressor of Cytokine Signaling 3 Protein / genetics
  • Suppressor of Cytokine Signaling 3 Protein / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • C5ar1 protein, mouse
  • Il6ra protein, mouse
  • Receptor, Anaphylatoxin C5a
  • Receptors, Complement
  • Receptors, Interleukin-6
  • Socs1 protein, mouse
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • complement C3a receptor
  • Kdr protein, mouse
  • Vascular Endothelial Growth Factor Receptor-2
  • PHLPP1 protein, mouse
  • Phosphoprotein Phosphatases
  • PTEN Phosphohydrolase
  • Pten protein, mouse