Extracellular Phosphorylation of TIMP-2 by Secreted c-Src Tyrosine Kinase Controls MMP-2 Activity.
Extracellular Phosphorylation of TIMP-2 by Secreted c-Src Tyrosine Kinase Controls MMP-2 Activity.
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DOI：
10.1016/j.isci.2018.02.004
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发表时间：
2018-03-23
期刊：
影响因子：
5.8
通讯作者：
Bourboulia D
中科院分区：
文献类型：
--
作者：
Sánchez-Pozo J;Baker-Williams AJ;Woodford MR;Bullard R;Wei B;Mollapour M;Stetler-Stevenson WG;Bratslavsky G;Bourboulia D
金属蛋白酶组织抑制剂2（TIMP-2）是基质金属蛋白酶2（MMP-2）的特异性内源性抑制剂，MMP-2是降解细胞外基质、促进肿瘤细胞侵袭的关键酶。虽然TIMP-2：MMP-2复合物控制蛋白水解，但这两种蛋白在细胞外空间中缔合的信号传导机制仍未确定。在这里，我们报告，TIMP-2是磷酸化的细胞外分泌的c-Src酪氨酸激酶。因此，Y 90的磷酸化显著增强TIMP-2作为MMP-2抑制剂的效力，并减弱活性酶的催化作用。TIMP-2磷酸化似乎也是其在体内与潜在酶proMMP-2相互作用所必需的。激酶或不可磷酸化的Y 90的缺乏消除了TIMP-2与潜在酶的结合，最终阻碍了proMMP-2的活化。总之，分泌的c-Src引起的TIMP-2磷酸化代表了控制MMP-2蛋白水解功能的关键细胞外调节机制。c-Src酪氨酸激酶磷酸化TIMP-2分泌的c-Src在细胞外磷酸化TIMP-2 TIMP-2 Y 90磷酸化促进与proMMP-2的细胞外相互作用TIMP-2的酪氨酸磷酸化调节proMMP-2加工和MMP-2活性生物化学;酶学;分子生物学
The tissue inhibitor of metalloproteinases 2 (TIMP-2) is a specific endogenous inhibitor of matrix metalloproteinase 2 (MMP-2), which is a key enzyme that degrades the extracellular matrix and promotes tumor cell invasion. Although the TIMP-2:MMP-2 complex controls proteolysis, the signaling mechanism by which the two proteins associate in the extracellular space remains unidentified. Here we report that TIMP-2 is phosphorylated outside the cell by secreted c-Src tyrosine kinase. As a consequence, phosphorylation at Y90 significantly enhances TIMP-2 potency as an MMP-2 inhibitor and weakens the catalytic action of the active enzyme. TIMP-2 phosphorylation also appears to be essential for its interaction with the latent enzyme proMMP-2 in vivo. Absence of the kinase or non-phosphorylatable Y90 abolishes TIMP-2 binding to the latent enzyme, ultimately hampering proMMP-2 activation. Together, TIMP-2 phosphorylation by secreted c-Src represents a critical extracellular regulatory mechanism that controls the proteolytic function of MMP-2. c-Src tyrosine kinase phosphorylates TIMP-2 Secreted c-Src phosphorylates TIMP-2 extracellularly TIMP-2 Y90 phosphorylation promotes extracellular interaction with proMMP-2 Tyrosine phosphorylation of TIMP-2 regulates proMMP-2 processing and MMP-2 activity Biochemistry; Enzymology; Molecular Biology
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影响因子：
16
作者：
Mollapour, Mehdi;Tsutsumi, Shinji;Donnelly, Alison C.;Beebe, Kristin;Tokita, Mari J.;Lee, Min-Jung;Lee, Sunmin;Morra, Giulia;Bourboulia, Dimitra;Scroggins, Bradley T.;Colombo, Giorgio;Blagg, Brian S.;Panaretou, Barry;Stetler-Stevenson, William G.;Trepel, Jane B.;Piper, Peter W.;Prodromou, Chrisostomos;Pearl, Laurence H.;Neckers, Len
通讯作者：
Neckers, Len
影响因子：
3.5
作者：
Lafleur, MA;Tester, AM;Thompson, EW
通讯作者：
Thompson, EW
影响因子：
4.8
作者：
Kinoshita, T;Sato, H;Seiki, M
通讯作者：
Seiki, M
影响因子：
3.7
作者：
Batra, Jyotica;Soares, Alexei S.;Radisky, Evette S.
通讯作者：
Radisky, Evette S.
DOI：
10.1073/pnas.102185399
发表时间：
2002-05-28
影响因子：
11.1
作者：
Morgunova, E;Tuuttila, A;Tryggvason, K
通讯作者：
Tryggvason, K