Ligand-induced recruitment of Na+/H+-exchanger regulatory factor to the PDGF (platelet-derived growth factor) receptor regulates actin cytoskeleton reorganization by PDGF
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- Ligand-induced recruitment of Na+/H+-exchanger regulatory factor to the PDGF (platelet-derived growth factor) receptor regulates actin cytoskeleton reorganization by PDGF
- Demoulin, JB; Seo, Jeong Kon; Ekman, S; Grapengiesser, E; Hellman, U; Ronnstrand, L; Heldin, CH
- Chemotaxis; Cytoskeleton; Ezrin-binding protein 50 (EBP50); Intracellular pH; Na+/H+ exchanger regulatory factor (NHERF); Platelet-derived growth factor (PDGF)
- Issue Date
- PORTLAND PRESS LTD
- BIOCHEMICAL JOURNAL, v.376, no., pp.505 - 510
- Proteins interacting with the human PDGF (platelet-derived growth factor) β-receptor were isolated using immobilized peptides derived from the receptor C-terminus as a bait. We identified two PDZ domain proteins, namely NHERF (Na+/H+ exchanger regulatory factor, also called EBP50) and NHERF2 (E3KARP, SIP-1, TKA-1), which have been shown previously to associate with the murine PDGF receptor [Maudsley, Zamah, Rahman, Blitzer, Luttrell, Lefkowitz and Hall (2000) Mol. Cell. Biol. 20, 8352-8363]. In porcine aortic endothelial cells and in fibroblasts, NHERF recruitment was induced by PDGF treatment, but the receptor kinase activity was not required for the formation of the complex, suggesting that NHERF was not recruited in a phosphotyrosine-dependent manner. Instead, the interaction was abolished by mutation of the consensus C-terminal PDZ-interacting domain of the receptor (Leu-1106 to Ala), or truncation of the last 75 amino acid residues of the receptor. Disruption of NHERF binding to the receptor enhanced actin filament reorganization, but did not affect PDGF-induced mitogenicity and chemotaxis. Although NHERF was initially characterized as a factor required for intracellular pH regulation by β2-adrenergic receptors, we observed that it was not involved in pH regulation by PDGF. Collectively, these results suggest that the ligand-induced association of NHERF PDZ domain with the PDGF receptor tyrosine kinase controls the extent of cytoskeleton reorganization in response to PDGF.
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