Activation of Src kinase by protein-tyrosine phosphatase-PEST in osteoclasts: comparative analysis of the effects of bisphosphonate and protein-tyrosine phosphatase inhibitor on Src activation in vitro.
Activation of Src kinase by protein-tyrosine phosphatase-PEST in osteoclasts: comparative analysis of the effects of bisphosphonate and protein-tyrosine phosphatase inhibitor on Src activation in vitro.
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DOI：
10.1002/jcp.21777
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发表时间：
2009-08
影响因子：
5.6
通讯作者：
Schaller MD
中科院分区：
文献类型：
--
作者：
Chellaiah MA;Schaller MD
PTP-PEST参与破骨细胞密封环形成的调节。在这篇文章中，我们已经显示了PTP-PEST对c-Src在Y 527的去磷酸化和在Y 418的催化位点的磷酸化的调节作用。通过PTP-PEST的过表达激活破骨细胞中的Src，导致Y 421处的corpine和Y294处的WASP磷酸化。结果，Src、corneum和Arp 2与WASP的相互作用也得到增强。此外，与对照组相比，PTP-PEST过表达的破骨细胞显示密封环和骨吸收活性的数量增加。表达组成型活性Src（527 YDF）的细胞模拟PTP-PEST介导的效应。用双膦酸盐阿仑膦酸盐或有效的PTP抑制剂PAO治疗破骨细胞，由于Y 527处的去磷酸化状态减少，导致Y 418处Src的活性和磷酸化降低。因此，在这些破骨细胞中，Src介导的coronin和WASP的磷酸化以及WASP coronin Arp 2复合物和密封环的形成减少。在用[C1] Src抑制剂PP 2处理的破骨细胞中观察到类似的效果。我们已经表明，二膦酸盐可以通过抑制PTP-PEST/Src介导的下游信号传导来调节破骨细胞的功能，除了其对小GTP结合蛋白如Rab、Rho和Rac的翻译后修饰的抑制作用之外，如其他人所示。抑制剂PP 2和PAO对破骨细胞功能的有希望的作用表明，骨转移和骨质疏松症患者的治疗方法可以替代双膦酸盐。
PTP–PEST is involved in the regulation of sealing ring formation in osteoclasts. In this article, we have shown a regulatory role for PTP–PEST on dephosphorylation of c-Src at Y527 and phosphorylation at Y418 in the catalytic site. Activation of Src in osteoclasts by over-expression of PTP–PEST resulted in the phosphorylation of cortactin at Y421 and WASP at Y294. Also enhanced as a result, is the interaction of Src, cortactin, and Arp2 with WASP. Moreover, the number of osteoclasts displaying sealing ring and bone resorbing activity was increased in response to PTP–PEST over-expression as compared with control osteoclasts. Cells expressing constitutively active-Src (527YDF) simulate the effects mediated by PTP–PEST. Treatment of osteoclasts with a bisphosphonate alendronate or a potent PTP inhibitor PAO decreased the activity and phosphorylation of Src at Y418 due to reduced dephosphorylation state at Y527. Therefore, Src-mediated phosphorylation of cortactin and WASP as well as the formation of WASP cortactin Arp2 complex and sealing ring were reduced in these osteoclasts. Similar effects were observed in osteoclasts treated with [C1]an Src inhibitor PP2. We have shown that bisphosphonates could modulate the function of osteoclasts by inhibiting downstream signaling mediated by PTP–PEST/Src, in addition to its effect on the inhibition of the post-translational modification of small GTP-binding proteins such as Rab, Rho, and Rac as shown by others. The promising effects of the inhibitors PP2 and PAO on osteoclast function suggest a therapeutic approach for patients with bone metastases and osteoporosis as an alternative to bisphosphonates.
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影响因子：
4.8
作者：
Chellaiah, MA;Soga, N;Hruska, KA
通讯作者：
Hruska, KA
DOI：
10.1083/jcb.148.4.665
发表时间：
2000-02-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chellaiah M;Kizer N;Silva M;Alvarez U;Kwiatkowski D;Hruska KA
通讯作者：
Hruska KA
DOI：
10.1084/jem.20030976
发表时间：
2004-01-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Badour K;Zhang J;Shi F;Leng Y;Collins M;Siminovitch KA
通讯作者：
Siminovitch KA
影响因子：
20.3
作者：
Calle, Y;Jones, GE;Thrasher, AJ
通讯作者：
Thrasher, AJ
影响因子：
3.3
作者：
Chellaiah, MA;Kizer, N;Hruska, KA
通讯作者：
Hruska, KA