Ligand-independent dimerization of PDGFR mutants

Stable Identifier
R-HSA-9672168
Type
Reaction [transition]
Species
Homo sapiens
Compartment
plasma membrane
ReviewStatus
5/5
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Ligand-independent dimerization of PDGFR mutants
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Activating missense and small in-frame deletion mutations in PDGFRA occur in some cancers, including KIT-mutant negative gastroinstestinal tumors (GIST) and haematological malignancies (Corless et al, 2005; Heinrich et al, 2003; Hirota et al, 2003; Poveda et al, 2017; reviewed in Roskoski, 2018; Klug et al, 2018). Mutations cluster in the autoinhibitory juxtamembrane domain or the kinase domain, but are also found at low frequency in the transmembrane domain (Heinrich et al, 2003; Corless et al, 2005; Velghe et al, 2014; Ip et al, 2018; reviewed in Klug et al, 2018). Most characterized gain-of-function PDGFRA mutants activate aberrant signaling by promoting ligand-independent dimerization and autophosphorylation (Heinrich et al, 2003; Corless et al, 2005; Velghe et al, 2014; reviewed in Klug et al, 2018).
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
29408302 The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders

Roskoski, R

Pharmacol. Res. 2018
12522257 PDGFRA activating mutations in gastrointestinal stromal tumors

Corless, CL, Heinrich, MC, Singer, S, Griffith, DJ, Town, A, Haley, A, Duensing, A, McGreevey, L, Fletcher, JA, Demetri, GD, Joseph, N, Chen, CJ, Fletcher, CD

Science 2003
12949711 Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors

Kitamura, Y, Shinomura, Y, Isozaki, K, Nishida, T, Kinoshita, K, Ohashi, A, Hirota, S

Gastroenterology 2003
28351781 GEIS guidelines for gastrointestinal sarcomas (GIST)

Romero, I, Martín-Broto, J, López-Guerrero, JA, Grupo Español de Investigación en Sarcomas/Spanish Group for Sarcoma Research, -, Martínez, V, Valverde, C, Poveda, A, García Del Muro, X, Cubedo, R, Serrano, C

Cancer Treat. Rev. 2017
29964125 Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Heinrich, MC, Kent, JD, Klug, LR

Pharmacol. Ther. 2018
15928335 PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib

Shiraga, S, McGreevey, L, Schroeder, A, Corless, CL, Heinrich, MC, Harrell, P, Morich, J, Bainbridge, T, Town, A, Griffith, D

J. Clin. Oncol. 2005
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
Participants
Input
Output
Participates
as an event of
Normal reaction
PDGF dimer binds two receptors simultaneously (Homo sapiens)
Functional status

Gain of function of PDGFR mutant receptors [plasma membrane]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
Authored
Rothfels, K  (2020-02-25)
Reviewed
Ip, CKM  (2020-02-06)
Created
Rothfels, K  (2019-12-23)
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