Ligand-independent dimerization of cytosolic PDGFRA and PDGFRB fusion proteins

Stable Identifier
Reaction [transition]
Homo sapiens
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Fusions of an N-terminal partner and the cytosolic domain of PDGFRA or PDGFRB occur at low frequency in some cancers, particularly haematological disease (Cools et al, 2003; Ozawa et al, 2010; Hidalgo-Curtis et al, 2010; reviewed in Wang et al, 2016; Appiah-Kubi et al, 2017). Fusion proteins are constitutively active in the absence of ligand. Constitutive activation is promoted in many cases by the presence of an oligomerization domain in the N-terminal fusion partner, which promotes dimerization and subsequent trans-autophosphorylation. This is not always the case, however. In the instance of FIP1L1-PDGFRA, for example, constitutive activation is independent of the FIP1L1 portion of the protein, and dimerization depends on the relief of PDGFRA autoinhibition through disruption of the juxtamembrane region (Stover et al, 2006; reviewed in Reilly, 2003; Appiah-Kubi et al, 2017).
Literature References
PubMed ID Title Journal Year
16690743 Activation of FIP1L1-PDGFRalpha requires disruption of the juxtamembrane domain of PDGFRalpha and is FIP1L1-independent

Marynen, P, Folens, C, Gilliland, DG, Williams, IR, Mentens, N, Cools, J, Stover, EH, Lee, BH, Chen, J

Proc. Natl. Acad. Sci. U.S.A. 2006
27170215 The platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are major players in oncogenesis, drug resistance, and attractive oncologic targets in cancer

Yao, X, Chen, Y, Wu, M, Qian, H, Wang, Y, Wu, Y, Appiah-Kubi, K

Growth Factors 2016
12660384 A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome

Marynen, P, Boogaerts, M, Griffin, JD, Galinsky, I, Cortes, J, Coutré, SE, Kantarjian, H, Schmid, J, Malone, J, Schrier, SL, Cools, J, Stover, EH, Wlodarska, I, Kutok, J, Rose, M, Verhoef, G, Vandenberghe, P, Gotlib, J, Gilliland, DG, Alam, R, Clark, J, Legare, RD, Cross, NC, Stone, R, Deangelo, DJ, Tefferi, A

N. Engl. J. Med. 2003
28010895 Platelet-derived growth factor receptors (PDGFRs) fusion genes involvement in hematological malignancies

Yao, X, Chen, Y, Wu, M, Qian, H, Wang, Y, Wu, Y, Appiah-Kubi, K, Lan, T

Crit. Rev. Oncol. Hematol. 2017
20085582 Fusion of PDGFRB to two distinct loci at 3p21 and a third at 12q13 in imatinib-responsive myeloproliferative neoplasms

Grand, FH, Hidalgo-Curtis, C, Apperley, JF, Stark, A, Jeng, M, Gotlib, J, Cross, NC, Stark, A, Chase, A

Br. J. Haematol. 2010
20889717 PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas

Ladanyi, M, Fomchenko, EI, Fujii, K, Brennan, CW, Tandon, A, Oka, H, Yasui, Y, Nakada, M, Wang, L, Sasayama, T, Holland, EC, Levine, RL, Pedraza, A, Utsuki, S, Huse, JT, Ozawa, T, Squatrito, M

Genes Dev. 2010
14556779 Receptor tyrosine kinases in normal and malignant haematopoiesis

Reilly, JT

Blood Rev. 2003
Functional status

Gain of function of cytosolic PDGFR fusions [cytosol]

Disease Entity
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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