Signaling by PDGFRA extracellular domain mutants

Stable Identifier
Homo sapiens
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Mutations in the extracellular domain of receptor tyrosine kinases like PDGRFA have the potential to interfere with glycosylation, which is required for proper trafficking to the cell surface. Versions of PDGFRA bearing mutations in the extracellular domain have been identified in some cancers, and while some of these are inactive, some have also been shown to signal constitutively from the endoplasmic reticulum (Ip et al, 2018; Velghe et al, 2014; Ozawa et al, 2010; Paugh et al, 2013; Clarke et al, 2003). PDGFRA Y288C carries a mutation in the extracellular domain of the receptor that prevents the normal trafficking of the protein to the plasma membrane. PDGFRA Y288C is trapped in the endoplasmic reticulum membrane, from where it is able to signal constitutively in the absence of ligand (Ip et al, 2018). Similarly, a version of PDGFRA bearing an in-frame deletion of exons 8 and 9 has been identified in glioblastoma. The resulting protein is constitutively active in the absence of ligand despite the low fraction of protein expressed at the cell surface (Clarke et al, 2003; Ozawa et al, 2010).
Literature References
PubMed ID Title Journal Year
30389923 Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapies

Vellano, CP, Scott, KL, Ju, Z, Jeong, KJ, Shao, SH, Leonard, PG, Woessner, R, Mills, GB, Sahni, N, Ip, CKM, Hua, X, Ng, PKS

Nat Commun 2018
12569364 A human brain tumor-derived PDGFR-alpha deletion mutant is transforming

Clarke, ID, Dirks, PB

Oncogene 2003
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
23970477 Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas

Diaz, AK, Zhang, J, Broniscer, A, Zhang, J, Zhu, X, Baker, SJ, Reis, RM, Endersby, R, Bax, DA, Carvalho, D, Wetmore, C, Qu, C, Ellison, DW, Jones, C, Paugh, BS, Onar-Thomas, A

Cancer Res. 2013
23752188 PDGFRA alterations in cancer: characterization of a gain-of-function V536E transmembrane mutant as well as loss-of-function and passenger mutations

Polyansky, AA, Hallberg, B, Van Cauwenberghe, S, Demoulin, JB, Montano-Almendras, CP, Chand, D, Velghe, AI, Essaghir, A, Charni, S

Oncogene 2014
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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