Reactome | PDGF dimer binds two receptors simultaneously

PDGF dimer binds two receptors simultaneously

Stable Identifier

R-HSA-186773

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

plasma membrane

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PDGF dimer binds two receptors simultaneously. The receptors dimerise on ligand binding and undergo conformational change which is key to receptor autophosphorylation (reviewed in Heldin et al, 1998). PDGFRA and PDGFRB activity can be inhibited by binding to type I and type II tyrosine kinase inhibitors (reviewed in Roskoski, 2018). Type I inhibitors such as crenolanib, avripatinib and pazopanib, bind to the active conformation of the receptor, while type II inhibitors like imatinib, sorafenib and others bind to the inactive conformation (Gril et al, 2013; Wang et al, 2014; Mathias et al, 2015; Meliau et al, 2017; Lombardo et al, 2004; Chen et al, 2006; Matsui et al, 2008; Liu et al, 2011; Hilberg et al, 2008; Hilberg et al, 2017; Wilhelm et al, 2002; Strumberg et al, 2005; Mendel et al, 2003; Roskoski, 2007). PDGFRA signaling can also be inhibited by the monoclonal antibody olaratumab, which interferes with binding of AA, BB and CC ligand to the receptor (Gerber et al, 2012; Loizos et al, 2005; Matei et al, 2006; Russell et al, 2010; Stock et al, 2007).

Literature References

PubMed ID	Title	Journal	Year
16436588	Potent inhibition of platelet-derived growth factor-induced responses in vascular smooth muscle cells by BMS-354825 (dasatinib) Chen, Z, Lee, FY, Bhalla, KN, Wu, J	Mol. Pharmacol.	2006
21251937	Inhibition of PDGF, TGF-β, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib Liu, Y, Wang, Z, Kwong, SQ, Lui, ELH, Friedman, SL, Li, FR, Lam, RWC, Zhang, GC, Zhang, H, Ye, T	J. Hepatol.	2011
29408302	The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders Roskoski, R	Pharmacol. Res.	2018
23583652	Pazopanib inhibits the activation of PDGFRβ-expressing astrocytes in the brain metastatic microenvironment of breast cancer cells Gril, B, Palmieri, D, Qian, Y, Anwar, T, Liewehr, DJ, Steinberg, SM, Andreu, Z, Masana, D, Fernández, P, Steeg, PS, Vidal-Vanaclocha, F	Am. J. Pathol.	2013
9739761	Signal transduction via platelet-derived growth factor receptors Heldin, CH, Ostman, A, Rönnstrand, L	Biochim Biophys Acta	1998
17604334	Platelet-derived growth factor receptor-alpha: a novel therapeutic target in human hepatocellular cancer Stock, P, Monga, D, Tan, X, Micsenyi, A, Loizos, N, Monga, SP	Mol. Cancer Ther.	2007
18559524	BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy Hilberg, F, Roth, GJ, Krssak, M, Kautschitsch, S, Sommergruber, W, Tontsch-Grunt, U, Garin-Chesa, P, Bader, G, Zoephel, A, Quant, J, Heckel, A, Rettig, WJ	Cancer Res.	2008
17943726	E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition Matsui, J, Yamamoto, Y, Funahashi, Y, Tsuruoka, A, Watanabe, T, Wakabayashi, T, Uenaka, T, Asada, M	Int J Cancer	2008
25328409	Crenolanib, a PDGFR inhibitor, suppresses lung cancer cell proliferation and inhibits tumor growth in vivo Wang, P, Song, L, Ge, H, Jin, P, Jiang, Y, Hu, W, Geng, N	Onco Targets Ther	2014
16331269	Autocrine activation of PDGFRalpha promotes the progression of ovarian cancer Matei, D, Emerson, RE, Lai, YC, Baldridge, LA, Rao, J, Yiannoutsos, C, Donner, DD	Oncogene	2006
12369853	BAY 43-9006: preclinical data Wilhelm, S, Chien, DS	Curr. Pharm. Des.	2002
15615512	Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays Lombardo, LJ, Lee, FY, Chen, P, Norris, D, Barrish, JC, Behnia, K, Castaneda, S, Cornelius, LA, Das, J, Doweyko, AM, Fairchild, C, Hunt, JT, Inigo, I, Johnston, K, Kamath, A, Kan, D, Klei, H, Marathe, P, Pang, S, Peterson, R, Pitt, S, Schieven, GL, Schmidt, RJ, Tokarski, J, Wen, ML, Wityak, J, Borzilleri, RM	J. Med. Chem.	2004
12538485	In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship Mendel, DB, Laird, AD, Xin, X, Louie, SG, Christensen, JG, Li, G, Schreck, RE, Abrams, TJ, Ngai, TJ, Lee, LB, Murray, LJ, Carver, J, Chan, E, Moss, KG, Haznedar, JO, Sukbuntherng, J, Blake, RA, Sun, L, Tang, C, Miller, T, Shirazian, S, McMahon, G, Cherrington, JM	Clin. Cancer Res.	2003
25597754	The FLT3 and PDGFR inhibitor crenolanib is a substrate of the multidrug resistance protein ABCB1 but does not inhibit transport function at pharmacologically relevant concentrations Mathias, TJ, Natarajan, K, Shukla, S, Doshi, KA, Singh, ZN, Ambudkar, SV, Baer, MR	Invest New Drugs	2015
22933705	Stromal platelet-derived growth factor receptor α (PDGFRα) provides a therapeutic target independent of tumor cell PDGFRα expression in lung cancer xenografts Gerber, DE, Gupta, P, Dellinger, MT, Toombs, JE, Peyton, M, Duignan, I, Malaby, J, Bailey, T, Burns, C, Brekken, RA, Loizos, N	Mol. Cancer Ther.	2012
29263244	Triple Angiokinase Inhibitor Nintedanib Directly Inhibits Tumor Cell Growth and Induces Tumor Shrinkage via Blocking Oncogenic Receptor Tyrosine Kinases Hilberg, F, Tontsch-Grunt, U, Baum, A, Le, AT, Doebele, RC, Lieb, S, Gianni, D, Voss, T, Garin-Chesa, P, Haslinger, C, Kraut, N	J. Pharmacol. Exp. Ther.	2018
17367763	Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor Roskoski, R	Biochem. Biophys. Res. Commun.	2007
28435517	Inhibition of the platelet-derived growth factor receptor beta (PDGFRB) using gene silencing, crenolanib besylate, or imatinib mesylate hampers the malignant phenotype of mesothelioma cell lines Melaiu, O, Catalano, C, De Santi, C, Cipollini, M, Figlioli, G, Pellè, L, Barone, E, Evangelista, M, Guazzelli, A, Boldrini, L, Sensi, E, Bonotti, A, Foddis, R, Cristaudo, A, Mutti, L, Fontanini, G, Gemignani, F, Landi, S	Genes Cancer	2017
16474853	Preclinical and clinical development of the oral multikinase inhibitor sorafenib in cancer treatment Strumberg, D	Drugs Today	2005
20813817	Targeting the {alpha} receptor for platelet-derived growth factor as a primary or combination therapy in a preclinical model of prostate cancer skeletal metastasis Russell, MR, Liu, Q, Fatatis, A	Clin. Cancer Res.	2010