Regulation of platelet-derived growth factor receptor function by integrin-associated cell surface transglutaminase.
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.
Zemskov
Evgeny A
EA
From the Department of Biochemistry and Molecular Biology, Baltimore, Maryland 21201; Center for Vascular and Inflammatory Diseases, Baltimore, Maryland 21201.
Loukinova
Elena
E
Center for Vascular and Inflammatory Diseases, Baltimore, Maryland 21201; Departments of Physiology, Baltimore, Maryland 21201.
Mikhailenko
Irina
I
Center for Vascular and Inflammatory Diseases, Baltimore, Maryland 21201; Departments of Physiology, Baltimore, Maryland 21201.
Coleman
Richard A
RA
Departments of Physiology, Baltimore, Maryland 21201.
Strickland
Dudley K
DK
Center for Vascular and Inflammatory Diseases, Baltimore, Maryland 21201; Surgery, Baltimore, Maryland 21201.
Belkin
Alexey M
AM
From the Department of Biochemistry and Molecular Biology, Baltimore, Maryland 21201; Center for Vascular and Inflammatory Diseases, Baltimore, Maryland 21201; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201. Electronic address: abelkin@som.umaryland.edu.
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology; D015536:Down-Regulation / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology* / Q000201:enzymology*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D011940:Receptor Aggregation / Q000502:physiology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology; D014945:Wound Healing / Q000502:physiology
D016023:Integrins; D011956:Receptors, Cell Surface; D011503:Transglutaminases; C105804:transglutaminase 1; D020797:Receptor, Platelet-Derived Growth Factor beta