Platelet-derived growth factor (PDGF)-induced activation of signal transducer and activator of transcription (Stat) 5 is mediated by PDGF beta-receptor and is not dependent on c-src, fyn, jak1 or jak2 kinases.
Platelet-derived growth factor (PDGF)-induced activation of signal transducer and activator of transcription (Stat) 5 is mediated by PDGF beta-receptor and is not dependent on c-src, fyn, jak1 or jak2 kinases.
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血小板源性生长因子 (PDGF) 诱导的信号转导子和转录激活子 (Stat) 5 的激活由 PDGF β 受体介导，不依赖于 c-src、fyn、jak1 或 jak2 激酶。
DOI：
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发表时间：
2000
影响因子：
4.1
通讯作者：
Olli Silvennoinen
中科院分区：
文献类型：
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作者：
K. Paukku;S. Valgeirsdóttir;P. Saharinen;Mathias Bergman;C. Heldin;Olli Silvennoinen
几种生长因子激活信号转导子和转录激活子（Stats），但Stats在受体酪氨酸激酶信号传导中的激活机制仍然难以捉摸。在本研究中，我们分析了不同的血小板源性生长因子（PDGF）诱导的酪氨酸激酶在激活Stat 5的作用。在昆虫和哺乳动物细胞中的共表达实验表明，PDGF β-受体（PDGF β-R）和Jak 1，但不是c-Src，诱导Stat 5的激活。此外，免疫复合物纯化的PDGF β-R能够直接磷酸化Stat 5。通过过度表达激酶阴性（KN）和野生型Jak和c-Src激酶，进一步研究了细胞质酪氨酸激酶在PDGF诱导的Stat 5活化中的作用。Jak 1-KN或Jak 2-KN没有影响，但Src-KN和野生型c-Src类似地降低了PDGF-β-R诱导的Stat 5活化。Src和Stat 5的激活依赖于PDGF β-R中相同的酪氨酸残基Tyr（579）和Tyr（581）;因此观察到的Src抑制可能是由于Stat 5与受体结合的竞争。最后，来源于Src（-/-）和Fyn（-/-）小鼠的成纤维细胞显示出PDGF诱导的Stat 5酪氨酸磷酸化的正常模式。总之，这些结果表明，Stat 5是PDGF β-R的直接底物，并且激活不需要Jak 1，Jak 2，c-Src或Fyn酪氨酸激酶。
Several growth factors activate signal transducers and activators of transcription (Stats) but the mechanism of Stat activation in receptor tyrosine kinase signalling has remained elusive. In the present study we have analysed the roles of different platelet-derived growth factor (PDGF)-induced tyrosine kinases in the activation of Stat5. Co-expression experiments in insect and mammalian cells demonstrated that both PDGF beta-receptor (PDGF beta-R) and Jak1, but not c-Src, induced the activation of Stat5. Furthermore, immune-complex-purified PDGF beta-R was able to phosphorylate Stat5 directly. The role of the cytoplasmic tyrosine kinases in the PDGF-induced activation of Stat5 was further investigated by overexpressing kinase-negative (KN) and wild-type Jak and c-Src kinases. Jak1-KN or Jak2-KN had no effect but both Src-KN and wild-type c-Src similarly decreased the PDGF-beta-R-induced activation of Stat5. The activation of both Src and Stat5 is dependent on the same tyrosine residues Tyr(579) and Tyr(581) in PDGF beta-R; thus the observed inhibition by Src might result from competition for binding of Stat5 to the receptor. Finally, fibroblasts derived from Src(-/-) and Fyn(-/-) mice showed normal pattern of PDGF-induced tyrosine phosphorylation of Stat5. Taken together, these results indicate that Stat5 is a direct substrate for PDGF beta-R and that the activation does not require Jak1, Jak2, c-Src or Fyn tyrosine kinases.