Idiopathic basal ganglia calcification-associated PDGFRB mutations impair the receptor signalling.
Idiopathic basal ganglia calcification-associated PDGFRB mutations impair the receptor signalling.
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DOI：
10.1111/jcmm.12443
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发表时间：
2015-01
影响因子：
5.3
通讯作者：
Demoulin JB
中科院分区：
文献类型：
--
作者：
Arts FA;Velghe AI;Stevens M;Renauld JC;Essaghir A;Demoulin JB
血小板衍生生长因子（PDGF）结合两种相关受体酪氨酸激酶，这两种受体由PDGFRA和PDGFRB基因编码。最近，在诊断为特发性基底神经节钙化（IBGC或Fahr病）的患者中发现了杂合PDGFRB突变，这是一种罕见的遗传性神经系统疾病。本研究的目的是确定这些突变是否对PDGFRB活性有积极或消极的影响。我们首先发现E1071V突变体的行为与野生型PDGFRB相似，并且可能代表与IBGC无关的多态性。相比之下，L658P突变体没有激酶活性，无法激活PDGF通常刺激的任何途径。R987W突变体激活了Akt和MAP激酶，但未诱导PDGF刺激后信号传导和转录激活因子3 （STAT3）的磷酸化。磷脂酶c - γ的磷酸化也降低。最后，我们发现与野生型PDGFRB相比，R987W突变体在PDGF结合后降解速度更快。总之，与IBGC相关的PDGFRB突变损害了受体信号传导。IBGC中PDGFRB功能丧失与最近描述的PDGF-B配体失活突变一致。这些结果引起了人们对伊马替尼等药物抑制PDGF受体的长期安全性的关注。
Platelet-derived growth factors (PDGF) bind to two related receptor tyrosine kinases, which are encoded by the PDGFRA and PDGFRB genes. Recently, heterozygous PDGFRB mutations have been described in patients diagnosed with idiopathic basal ganglia calcification (IBGC or Fahr disease), a rare inherited neurological disorder. The goal of the present study was to determine whether these mutations had a positive or negative impact on the PDGFRB activity. We first showed that the E1071V mutant behaved like wild-type PDGFRB and may represent a polymorphism unrelated to IBGC. In contrast, the L658P mutant had no kinase activity and failed to activate any of the pathways normally stimulated by PDGF. The R987W mutant activated Akt and MAP kinases but did not induce the phosphorylation of signal transducer and activator of transcription 3 (STAT3) after PDGF stimulation. Phosphorylation of phospholipase Cγ was also decreased. Finally, we showed that the R987W mutant was more rapidly degraded upon PDGF binding compared to wild-type PDGFRB. In conclusion, PDGFRB mutations associated with IBGC impair the receptor signalling. PDGFRB loss of function in IBGC is consistent with recently described inactivating mutations in the PDGF-B ligand. These results raise concerns about the long-term safety of PDGF receptor inhibition by drugs such as imatinib.
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DOI：
10.1016/j.bbamcr.2013.11.024
发表时间：
2014-02-01
影响因子：
5.1
作者：
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通讯作者：
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影响因子：
5.3
作者：
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影响因子：
3.1
作者：
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通讯作者：
Hannequin, Didier
影响因子：
12.7
作者：
Miklossy, J;Mackenzie, IR;McGeer, PL
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