Autophosphorylation of PDGF alpha receptors

Receptor dimerisation is key event in PDGF receptor activation. The intracellular regions of the receptors are juxtaposed which allows trans-phosphorylation between the two receptors in the complex.<br>The autophosphorylation site Y857 located inside the kinase domain of beta-receptor (PDGFRB) is important for activation of the kinase. This tyrosine is conserved in the alpha-receptor (PDGFRA), where it corresponsds to Y849, and in almost all other tyrosine kinase receptors. The other known autophosphorylation sites are localized outside the kinase domains of the alpha- and beta- receptors; of the 15( beta) or 16 (alpha) tyrosine residues in the intracellular, non-catalytic part of the beta- or alpha receptor, 11 and 10, respectively, are autophosphorylation sites (reviewed in Heldin et al, 1998).<br>PDGFRA and PDGFRB activity can be inhibited by binding to type I and type II tyrosine kinase inhibitors (reviewed in Roskoski, 2018). Type I inhibitors such as crenolanib, avripatinib and pazopanib, bind to the active conformation of the receptor and inhibit trans-autophosphorylation (Ip et al, 2018; Evans et al, 2017; Davids et al, 2009; reviewed in Roskoski, 2018; Klug et al, 2018; Papadopoulos and Lennartsson, 2016).<br>

受体的二聚化是血小板衍生生长因子受体（PDGF受体）激活中的关键事件。受体的细胞内区域相互毗邻，这使得在复合物中两个受体之间可以发生跨膜磷酸化。位于β受体（PDGFRB）激酶域内的自磷酸化位点Y857对于激酶的激活至关重要。这种酪氨酸在α受体（PDGFRA）中得以保守，对应于Y849，以及几乎所有的其他酪氨酸激酶受体。其他已知的自磷酸化位点位于α和β受体的激酶域之外；在β或α受体的细胞内非催化部分中，共有15（β型）或16（α型）酪氨酸残基中，分别有11和10个是自磷酸化位点（参见Heldin等，1998年的综述）。PDGFRA和PDGFRB的活性可以通过与I型和II型酪氨酸激酶抑制剂的结合来抑制（参见Roskoski，2018年的综述）。I型抑制剂，如crenolanib、avripatinib和pazopanib，与受体的活性构象结合并抑制跨自磷酸化（参见Ip等，2018年；Evans等，2017年；Davids等，2009年；参见Roskoski，2018年；Klug等，2018年；Papadopoulos和Lennartsson，2016年的综述）。