Noonan syndrome-associated SHP-2/Ptpn11 mutants enhance SIRPα and PZR tyrosyl phosphorylation and promote adhesion-mediated ERK activation
Noonan syndrome-associated SHP-2/Ptpn11 mutants enhance SIRPα and PZR tyrosyl phosphorylation and promote adhesion-mediated ERK activation
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DOI：
10.1074/jbc.m801382200
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发表时间：
2008-05-30
影响因子：
4.8
通讯作者：
Bennett, Anton M.
中科院分区：
文献类型：
--
作者：
Eminaga, Seda;Bennett, Anton M.
努南综合征 (NS) 是一种常染色体显性遗传疾病，与多种发育异常相关。据报道，大约 50% 的 NS 病例中存在蛋白质酪氨酸磷酸酶 SHP-2/PTPN11 的激活突变。尽管被激活，NS 相关的 SHP-2 突变体仍需要质膜接近才能引发疾病相关信号传导。在这里，我们发现 NS 相关的 SHP-2 突变体诱导跨膜糖蛋白、SIRP α（信号调节蛋白 α）和 PZR（蛋白零相关）的高酪氨酸磷酸化，导致它们与 NS 相关的 SHP-2 突变体的关联增加。 NS 相关的 SHP-2 突变体通过削弱 SIRP α 去磷酸化或促进 PZR 酪氨酰磷酸化来增强 SIRP α 和 PZR 酪氨酰磷酸化。重要的是，在 NS 小鼠模型的胚胎发生过程中，SIRP α 和 PZR 被过度酪氨酰磷酸化，并与 NS 相关的 SHP-2 突变体结合水平升高。 SIRP α 和 PZR 与细胞外基质依赖性信号传导有关。来自 NS 小鼠模型的小鼠胚胎成纤维细胞在纤连蛋白铺板反应中表现出增强的 ERK 激活。这些细胞中 SIRP α 和 PZR 的敲低减弱了纤连蛋白铺板后 ERK 的增强激活。因此，SIRP α 和 PZR 作为支架，促进 NS 相关 SHP-2 突变体的质膜募集和信号传导。
Noonan syndrome (NS) is an autosomal dominant disorder that is associated with multiple developmental abnormalities. Activated mutations of the protein-tyrosine phosphatase, SHP-2/PTPN11, have been reported in similar to 50% of NS cases. Despite being activated, NS-associated SHP-2 mutants require plasma membrane proximity to evoke disease-associated signaling. Here we show that NS-associated SHP-2 mutants induce hypertyrosyl phosphorylation of the transmembrane glycoproteins, SIRP alpha (signal-regulatory protein alpha) and PZR (protein zero-related), resulting in their increased association with NS-associated SHP-2 mutants. NS-associated SHP-2 mutants enhanced SIRP alpha and PZR tyrosyl phosphorylation either by impairing SIRP alpha dephosphorylation or by promoting PZR tyrosyl phosphorylation. Importantly, during embryogenesis in a mouse model of NS, SIRP alpha and PZR were hypertyrosyl-phosphorylated and bound increased levels of the NS-associated SHP-2 mutant. SIRP alpha and PZR have been implicated in extracellular matrix-dependent signaling. Mouse embryonic fibroblasts derived from a mouse model of NS displayed enhanced ERK activation in response to fibronectin plating. Knockdown of SIRP alpha and PZR in these cells attenuated the enhanced activation of ERK following fibronectin plating. Thus, SIRP alpha and PZR serve as scaffolds that facilitate plasma membrane recruitment and signaling of NS-associated SHP-2 mutants.