c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression.
c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression.
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c-Abl 通过差异调节经典和非经典 BMP 途径以及 p16INK4a 表达来促进成骨细胞扩张
DOI：
10.1038/ncb2528
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发表时间：
2012-06-24
影响因子：
21.3
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Kua HY;Liu H;Leong WF;Li L;Jia D;Ma G;Hu Y;Wang X;Chau JF;Chen YG;Mishina Y;Boast S;Yeh J;Xia L;Chen GQ;He L;Goff SP;Li B
干细胞更新或祖细胞扩增缺陷是骨质疏松症等衰老相关疾病的基础。然而，关于调节祖细胞扩增的机制仍不清楚。在这里，我们表明酪氨酸激酶c-Abl在骨祖细胞扩张中起着重要作用。c-Abl与BMPRIA相互作用并使其磷酸化，磷酸化差异性地影响BMPRIA与BMPRII和Tab 1-Tak 1复合物的相互作用，导致Smad 1/5/8和Erk 1/2的不均匀激活，这是指导p16 INK 4a表达的经典和非经典BMP途径。c-Abl缺陷使BMP信号从Smad 1/5/8转向Erk 1/2，导致p16 INK 4a上调和成骨细胞衰老。小鼠遗传学研究表明，p16 INK 4a控制间充质干细胞的维持和成骨细胞的扩增，并介导c-Abl缺乏对成骨细胞扩增和骨形成的影响。这些发现确定c-Abl作为BMP信号通路的调节剂，并揭示c-Abl在p16 INK 4a表达和骨祖细胞扩增中的作用。
Defects in stem cell renewal or progenitor cell expansion underlie ageing-related diseases such as osteoporosis. Yet much remains unclear about the mechanisms regulating progenitor expansion. Here we show that the tyrosine kinase c-Abl plays an important role in osteoprogenitor expansion. c-Abl interacts with and phosphorylates BMPRIA and the phosphorylation differentially influences the interaction of BMPRIA with BMPRII and the Tab1-Tak1 complex, leading to uneven activation of Smad1/5/8 and Erk1/2, the canonical and non-canonical BMP pathways that direct the expression of p16INK4a. c-Abl deficiency shunts BMP signalling from Smad1/5/8 to Erk1/2, leading to p16INK4a upregulation and osteoblast senescence. Mouse genetic studies revealed that p16INK4a controls mesenchymal stem cell maintenance and osteoblast expansion and mediates the effects of c-Abl deficiency on osteoblast expansion and bone formation. These findings identify c-Abl as a regulator of BMP signalling pathways and uncover a role for c-Abl in p16INK4a expression and osteoprogenitor expansion.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
16.2
作者：
Koleske, AJ;Gifford, AM;Baltimore, D
通讯作者：
Baltimore, D
DOI：
10.1126/stke.2002.151.pe40
发表时间：
2002-09-24
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
--
作者：
Miyazono, Kohei;Miyazawa, Keiji
通讯作者：
Miyazawa, Keiji
影响因子：
64.5
作者：
Kawahara TL;Michishita E;Adler AS;Damian M;Berber E;Lin M;McCord RA;Ongaigui KC;Boxer LD;Chang HY;Chua KF
通讯作者：
Chua KF
影响因子：
64.8
作者：
Janzen, Viktor;Forkert, Randolf;Scadden, David T.
通讯作者：
Scadden, David T.