Smad phosphoisoform signaling specificity: the right place at the right time.
Smad phosphoisoform signaling specificity: the right place at the right time.
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DOI：
10.1093/carcin/bgr172
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发表时间：
2011-11
期刊：
影响因子：
4.7
通讯作者：
Matsuzaki K
中科院分区：
文献类型：
--
作者：
Matsuzaki K
转化生长因子（TGF）-β在上皮再生期间拮抗促有丝分裂Ras信号传导，但TGF-β和Ras在驱动肿瘤进展中协同作用。对这些明显矛盾的影响的见解来自最近对TGF-β信号传导过程的详细分析。在此，我们总结了正常上皮和肿瘤中TGF-β/Ras信号传导的不同模式，并展示了Ras对TGF-β信号传导的干扰如何在肿瘤进展过程中导致TGF-β活性从肿瘤抑制转变为促肿瘤发生。将信号从TGF-β受体传递到细胞核的Smad蛋白在保守的Mad同源性（MH）1和MH 2结构域之间具有中间接头区域。TGF-β I型受体和Ras相关激酶差异磷酸化Smad 2和Smad 3以产生C-末端（C）、接头（L）或双重（L/C）磷酸化（p）同种型。在上皮稳态中，TGF-β介导的pSmad 3C信号传导对抗由促有丝分裂信号诱导的增殖反应。在癌变过程中，细胞质Ras相关激酶（包括丝裂原活化蛋白激酶）的活化通过将Smad 3信号从肿瘤抑制性pSmad 3C转移到致癌性pSmad 3L途径，从而对良性肿瘤赋予选择性优势，导致原位癌。最后，在侵入邻近组织的晚期癌的边缘，核Ras相关激酶如细胞周期蛋白依赖性激酶与细胞质激酶一起将TGF-β信号改变为更具侵袭性和增殖性的pSmad 2L/C和pSmad 3L/C信号传导。总之，TGF-β信号传导特异性来自Smad磷酸化同种型的时空动力学。基于这些发现，我们有理由希望，药物抑制连接磷酸化可能会通过从促肿瘤转化为肿瘤抑制TGF-β信号传导来抑制人类晚期癌症的进展。
Transforming growth factor (TGF)-β antagonizes mitogenic Ras signaling during epithelial regeneration, but TGF-β and Ras act synergistically in driving tumor progression. Insights into these apparently contradictory effects have come from recent detailed analyses of the TGF-β signaling process. Here, we summarize the different modes of TGF-β/Ras signaling in normal epithelium and neoplasms and show how perturbation of TGF-β signaling by Ras may contribute to a shift from tumor-suppressive to protumorigenic TGF-β activity during tumor progression. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between conserved Mad homology (MH) 1 and MH2 domains. TGF-β Type I receptor and Ras-associated kinases differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. In epithelial homeostasis, TGF-β-mediated pSmad3C signaling opposes proliferative responses induced by mitogenic signals. During carcinogenesis, activation of cytoplasmic Ras-associated kinases including mitogen-activated protein kinase confers a selective advantage on benign tumors by shifting Smad3 signaling from a tumor-suppressive pSmad3C to an oncogenic pSmad3L pathway, leading to carcinoma in situ. Finally, at the edges of advanced carcinomas invading adjacent tissues, nuclear Ras-associated kinases such as cyclin-dependent kinases, together with cytoplasmic kinases, alter TGF-β signals to more invasive and proliferative pSmad2L/C and pSmad3L/C signaling. Taken together, TGF-β signaling specificity arises from spatiotemporal dynamics of Smad phosphoisoforms. Based on these findings, we have reason to hope that pharmacologic inhibition of linker phosphorylation might suppress progression to human advanced carcinomas by switching from protumorigenic to tumor-suppressive TGF-β signaling.
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影响因子：
120.7
作者：
Chen, CJ;Yang, HI;Iloeje, UH
通讯作者：
Iloeje, UH
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Engel, ME;McDonnell, MA;Moses, HL
通讯作者：
Moses, HL
影响因子：
16
作者：
Feng, XH;Liang, YY;Lin, X
通讯作者：
Lin, X
DOI：
10.1073/pnas.150006697
发表时间：
2000-08-15
影响因子：
11.1
作者：
Claassen, GF;Hann, SR
通讯作者：
Hann, SR