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Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase | |
2015 | |
发表期刊 | JOURNAL OF BIOLOGICAL CHEMISTRY |
ISSN | 0021-9258 |
EISSN | 1083-351X |
卷号 | 290期号:26页码:15934-15947 |
发表状态 | 已发表 |
DOI | 10.1074/jbc.M115.651703 |
摘要 | Background: The view that, unlike kinases, phosphatases are nonspecific pervades the field. Results: PTP1B inhibited BRK by dephosphorylating Tyr-342, but activated SRC by antagonizing PAG-dependent inhibition by CSK. Conclusion: Signaling is regulated by combinatorial effects of PTKs and PTPs, with both enzyme classes displaying exquisite specificity. Significance: Defining phosphatase substrate specificity will reveal new, more effective strategies for therapeutic intervention in major human diseases. Despite significant evidence to the contrary, the view that phosphatases are nonspecific still pervades the field. Systems biology approaches to defining how signal transduction pathways are integrated at the level of whole organisms also often downplay the contribution of phosphatases, defining them as erasers that serve merely to restore the system to its basal state. Here, we present a study that counteracts the idea of nonspecific phosphatases. We have characterized two structurally similar and functionally related kinases, BRK and SRC, which are regulated by combinations of activating autophosphorylation and inhibitory C-terminal sites of tyrosine phosphorylation. We demonstrated specificity at the level of the kinases in that SRMS phosphorylated the C terminus of BRK, but not SRC; in contrast, CSK is the kinase responsible for C-terminal phosphorylation of SRC, but not BRK. For the phosphatases, we observed that RNAi-mediated suppression of PTP1B resulted in opposing effects on the activity of BRK and SRC and have defined the mechanisms underlying this specificity. PTP1B inhibited BRK by directly dephosphorylating the Tyr-342 autophosphorylation site. In contrast, PTP1B potentiated SRC activity, but not by dephosphorylating SRC itself directly; instead, PTP1B regulated the interaction between CBP/PAG and CSK. SRC associated with, and phosphorylated, the transmembrane protein CBP/PAG at Tyr-317, resulting in CSK recruitment. We identified PAG as a substrate of PTP1B, and dephosphorylation abolished recruitment of the inhibitory kinase CSK. Overall, these findings illustrate how the combinatorial effects of PTKs and PTPs may be integrated to regulate signaling, with both classes of enzymes displaying exquisite specificity. |
关键词 | phosphorylation phosphotyrosine Src tyrosine-protein kinase (tyrosine kinase) tyrosine-protein phosphatase (tyrosine phosphatase) PTP1B SRC BRK CSK and CBP PAG |
URL | 查看原文 |
收录类别 | SCI |
WOS研究方向 | Biochemistry & Molecular Biology |
WOS类目 | Biochemistry & Molecular Biology |
WOS记录号 | WOS:000356930100004 |
WOS关键词 | FAMILY KINASE ; INSULIN-RECEPTOR ; GROWTH-FACTOR ; SUBSTRATE RECOGNITION ; ADAPTER PROTEIN ; LIPID RAFTS ; SH3 DOMAIN ; 1B ; ACTIVATION ; BRK |
原始文献类型 | Article |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/120106 |
专题 | 个人在本单位外知识产出 |
通讯作者 | Miller, W. Todd; Tonks, Nicholas K. |
作者单位 | 1.Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA 2.SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY 11794 USA |
推荐引用方式 GB/T 7714 | Fan, Gaofeng,Aleem, Saadat,Yang, Ming,et al. Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2015,290(26):15934-15947. |
APA | Fan, Gaofeng,Aleem, Saadat,Yang, Ming,Miller, W. Todd,&Tonks, Nicholas K..(2015).Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase.JOURNAL OF BIOLOGICAL CHEMISTRY,290(26),15934-15947. |
MLA | Fan, Gaofeng,et al."Protein-tyrosine Phosphatase and Kinase Specificity in Regulation of SRC and Breast Tumor Kinase".JOURNAL OF BIOLOGICAL CHEMISTRY 290.26(2015):15934-15947. |
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