Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants

PDGFRA is subject to activating mutations in a number of cancers, including gastrointestinal stromal tumors (GIST), melanoma and haematological cancers (reviewed in Corless et al, 2011; Wang et al, 2016; Roskoski, 2018). The most prevalent mutations in PDGFRA are at residue V561 in the juxtamembrane domain, N659 in the small lobe of the kinase domain and D842 in the activation loop of the kinase domain. PDGFRA is also subject to short deletions in the activation loop segment (reviewed in Roskoski, 2018). Acitvated forms of the protein may signal from the plasma membrane, similar to the wild type receptor, however there is also evidence that some mutants, notably D842V and V561D localize primarily to the Golgi membrane. Activated PDGFRA mutants signal constitutively in the absence of ligand (reviewed in Roskoski, 2018; Wang et al, 2016; Klug et al, 2018).