Inactivation of Smad-transforming growth factor β signaling by Ca2+-calmodulin-dependent protein kinase II
Inactivation of Smad-transforming growth factor β signaling by Ca2+-calmodulin-dependent protein kinase II
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DOI：
10.1128/mcb.20.21.8103-8111.2000
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发表时间：
2000-11-01
影响因子：
5.3
通讯作者：
Chantry, A
中科院分区：
文献类型：
--
作者：
Wicks, SJ;Lui, S;Chantry, A
转化生长因子β（TGF-β）家族的成员通过Smad蛋白发出信号。Smad信号可以通过Ras/Erk/丝裂原活化蛋白途径来调节，以响应受体酪氨酸激酶活化和γ干扰素途径，并且还通过Smad 2与Ca 2 +-钙调蛋白的功能相互作用来调节。在这里，我们报告了Smad-TGF-β依赖性转录反应被组成性活化的Ca 2 +-钙调蛋白依赖性蛋白激酶II（Cam激酶II）的表达所阻止。Smad 2是Cam激酶II在体外丝氨酸-110、-240和-260处的靶底物。Cam激酶II。诱导Smad 2和Smad 4的体内磷酸化，并在较小程度上诱导Smad 3的体内磷酸化。当与Cam激酶II共表达并通过激活血小板衍生生长因子受体、表皮生长因子受体、HER 2（c-erbB 2）和TGF-β受体时，针对Smad 2磷酸丝氨酸-240产生的磷酸肽抗血清与Smad 2在体内反应。此外，凸轮激酶II阻断核积累的Smad 2和诱导Smad 2-Smad 4异寡聚化独立的TGF-β受体激活？同时阻止TGF-β依赖的Smad 2-Smad 3相互作用。这些发现提供了一种新的串扰机制，通过该机制，多种生长因子受体下游激活的Ca 2+依赖性激酶拮抗细胞对TGF-β的反应。
Members of the transforming growth factor beta (TGF-beta) family transduce signals through Smad proteins. Smad signaling can be regulated by the Ras/Erk/mitogen-activated protein pathway in response to receptor tyrosine kinase activation and the gamma interferon pathway and also by the functional interaction of Smad2 with Ca2+-calmodulin, Here we report that Smad-TGF-beta-dependent transcriptional responses are prevented by expression of a constitutively activated Ca2+-calmodulin-dependent protein kinase II (Cam kinase II). Smad2 is a target substrate for Cam kinase II in vitro at serine-110, -240, and -260. Cam kinase II. induces in vivo phosphorylation of Smad2 and Smad4 and, to a lesser extent, Smad3, A phosphopeptide antiserum raised against Smad2 phosphoserine-240 reacted with Smad2 in vivo when coexpressed with Cam kinase II and by activation of the platelet-derived growth factor receptor, the epidermal growth factor receptor, HER2 (c-erbB2), and the TGF-beta receptor. Furthermore, Cam kinase II blocked nuclear accumulation of a Smad2 and induced Smad2-Smad4 hetero-oligomerization independently of TGF-beta receptor activation? while preventing TGF-beta-dependent Smad2-Smad3 interactions. These findings provide a novel cross-talk mechanism by which Ca2+-dependent kinases activated downstream of multiple growth factor receptors antagonize cell responses to TGF-beta.