Regulation of Platelet-derived Growth Factor Receptor Function by Integrin-associated Cell Surface Transglutaminase

• Published in: The Journal of biological chemistry Vol. 284; no. 24; pp. 16693 - 16703
• Main Authors: Zemskov, Evgeny A., Loukinova, Elena, Mikhailenko, Irina, Coleman, Richard A., Strickland, Dudley K., Belkin, Alexey M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.06.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Adhesion - physiology; Cell Division - physiology; Cell Movement - physiology; Cells, Cultured; Dermis - cytology; Down-Regulation - physiology; Fibroblasts - cytology; Fibroblasts - enzymology; Humans; Integrins - metabolism; Mechanisms of Signal Transduction; Mice; NIH 3T3 Cells; Receptor Aggregation - physiology; Receptor, Platelet-Derived Growth Factor beta - genetics; Receptor, Platelet-Derived Growth Factor beta - metabolism; Receptors, Cell Surface - metabolism; Signal Transduction - physiology; Transglutaminases - genetics; Transglutaminases - metabolism; Up-Regulation - physiology; Wound Healing - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.010769

A functional collaboration between growth factor receptors such as platelet derived growth factor receptor (PDGFR) and integrins is required for effective signal transduction in response to soluble growth factors. However, the mechanisms of synergistic PDGFR/integrin signaling remain poorly understood. Our previous work showed that cell surface tissue transglutaminase (tTG) induces clustering of integrins and amplifies integrin signaling by acting as an integrin binding adhesion co-receptor for fibronectin. Here we report that in fibroblasts tTG enhances PDGFR-integrin association by interacting with PDGFR and bridging the two receptors on the cell surface. The interaction between tTG and PDGFR reduces cellular levels of the receptor by accelerating its turnover. Moreover, the association of PDGFR with tTG causes receptor clustering, increases PDGF binding, promotes adhesion-mediated and growth factor-induced PDGFR activation, and up-regulates downstream signaling. Importantly, tTG is required for efficient PDGF-dependent proliferation and migration of fibroblasts. These results reveal a previously unrecognized role for cell surface tTG in the regulation of the joint PDGFR/integrin signaling and PDGFR-dependent cell responses.