Pdgfra, short for platelet-derived growth factor receptor alpha, is a receptor tyrosine-kinase that plays crucial roles in various biological processes. It is activated by platelet-derived growth subunit A (PDGFA) and is involved in cell growth, differentiation, migration, and survival. The PDGFA/PDGFRA signaling pathway is important in embryonic development, tissue repair, and maintaining tissue homeostasis [2].

In the context of diseases, in idiopathic pulmonary fibrosis, Pdgfra+ lipofibroblasts (LipoFBs) are essential for the lung injury response. After bleomycin-induced lung injury in mice, injured LipoFBs acquire fibrogenic pathway activity while attenuating lipogenic pathways, potentially contributing to dysregulated repair and fibrosis [1]. In glioblastoma, PDGFA-induced signaling may involve EPHA2 in addition to PDGFRA, and co-upregulation of PDGFRA and EPHA2 is associated with worse patient prognosis and resistance to PDGFRA inhibitor [2]. In gastrointestinal stromal tumors (GISTs), approximately 90% are driven by activating mutations in KIT or PDGFRA. Secondary mutations in PDGFRA often lead to resistance to first-line imatinib treatment [3]. Avapritinib, a KIT and PDGFRA inhibitor, shows antitumor activity in advanced PDGFRA D842V-mutant GISTs [4,6]. In tendon regeneration, Tppp3+Pdgfra+ cells act as tendon stem cells, and inactivation of Pdgfra in these cells blocks tendon regeneration. However, Tppp3-Pdgfra+ fibro-adipogenic progenitors can give rise to fibrotic cells in healing tendons [5].

In conclusion, Pdgfra is crucial for normal biological functions such as tissue repair and stem cell maintenance. Through gene-knockout or conditional-knockout mouse models and other in vivo studies, its roles in diseases like pulmonary fibrosis, glioblastoma, GISTs, and tendon fibrosis have been revealed. Understanding Pdgfra's functions provides potential therapeutic targets for these diseases.

References:

1. Trempus, Carol S, Papas, Brian N, Sifre, Maria I, Perl, Anne K, Garantziotis, Stavros. 2023. Functional Pdgfra fibroblast heterogeneity in normal and fibrotic mouse lung. In JCI insight, 8, . doi:10.1172/jci.insight.164380. https://pubmed.ncbi.nlm.nih.gov/37824216/

2. Gai, Qu-Jing, Fu, Zhen, He, Jiang, Bian, Xiu-Wu, Wang, Yan. 2022. EPHA2 mediates PDGFA activity and functions together with PDGFRA as prognostic marker and therapeutic target in glioblastoma. In Signal transduction and targeted therapy, 7, 33. doi:10.1038/s41392-021-00855-2. https://pubmed.ncbi.nlm.nih.gov/35105853/

3. Cicala, Carlo María, Olivares-Rivas, Iván, Aguirre-Carrillo, Jon Ander, Serrano, César. 2024. KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem. In Expert opinion on investigational drugs, 33, 159-170. doi:10.1080/13543784.2024.2318317. https://pubmed.ncbi.nlm.nih.gov/38344849/

4. Heinrich, Michael C, Jones, Robin L, von Mehren, Margaret, Bauer, Sebastian, George, Suzanne. . Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. In The Lancet. Oncology, 21, 935-946. doi:10.1016/S1470-2045(20)30269-2. https://pubmed.ncbi.nlm.nih.gov/32615108/

5. Harvey, Tyler, Flamenco, Sara, Fan, Chen-Ming. 2019. A Tppp3+Pdgfra+ tendon stem cell population contributes to regeneration and reveals a shared role for PDGF signalling in regeneration and fibrosis. In Nature cell biology, 21, 1490-1503. doi:10.1038/s41556-019-0417-z. https://pubmed.ncbi.nlm.nih.gov/31768046/

6. Smrke, Alannah, Gennatas, Spyridon, Huang, Paul, Jones, Robin L. 2020. Avapritinib in the treatment of PDGFRA exon 18 mutated gastrointestinal stromal tumors. In Future oncology (London, England), 16, 1639-1646. doi:10.2217/fon-2020-0348. https://pubmed.ncbi.nlm.nih.gov/32517495/