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

doi:10.1074/jbc.M109.010769

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

From the ^‡Department of Biochemistry and Molecular Biology,
^§Center for Vascular and Inflammatory Diseases,
Departments of ^¶Physiology and
^‖Surgery, and
**Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201

¹ To whom correspondence should be addressed:
800 West Baltimore St., Baltimore, MD 21201.
Fax: 410-706-8121; E-mail: abelkin{at}som.umaryland.edu.

Abstract

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.

Footnotes

↵* This work was supported, in whole or in part, by National Institutes of Health Grants GM62895 (to A. M. B.) and HL50784 and HL54710 (to D. K. S.).
↵ The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4.
↵2 The abbreviations used are:

ECM

extracellular matrix

GFR

growth factor receptor

PDGFR

platelet-derived growth factor (PDGF) receptor

tTG

tissue transglutaminase

NHDF

normal human dermal fibroblasts

DSP

dithiobis(succinimidyl propionate)

DTSSP

dithiobis(sulfosuccinimidyl) propionate

Bis/Tris

2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol

shRNA

short hairpin RNA

mAb

monoclonal antibody

ERK

extracellular signal-regulated kinase

FGFR

fibroblast growth factor (FGF) receptor.
- Received March 17, 2009.
- Revision received April 20, 2009.