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

Authors

Michael G. Strainic, Department of Pathology, Case Western Reserve University, Cleveland, OhioCase Western Reserve University School of Medicine, Cleveland, Ohio
Elliot Pohlmann, Department of Pathology, Case Western Reserve University, Cleveland, OhioCase Western Reserve University School of Medicine, Cleveland, Ohio
Christopher C. Valley, Department of Pathology and Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
Ajay Sammeta, Department of Pathology, Case Western Reserve University, Cleveland, OhioCase Western Reserve University School of Medicine, Cleveland, Ohio
Wasim Hussain, Department of Pathology, Case Western Reserve University, Cleveland, OhioCase Western Reserve University School of Medicine, Cleveland, Ohio
Diane S. Lidke, Department of Pathology and Comprehensive Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, New Mexico
M Edward Medof, Department of Pathology, Case Western Reserve University, Cleveland, OhioCase Western Reserve University School of Medicine, Cleveland, Ohio

Document Type

Article

Publication Date

2-1-2020

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.

Recommended Citation

Strainic MG, Pohlmann E, Valley CC, Sammeta A, Hussain W, Lidke DS, Medof ME. 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. PMID: 31908021; PMCID: PMC7111459.