Protein kinase A, Ca2+/calmodulin-dependent kinase II, and calcineurin regulate the intracellular trafficking of myopodin between the Z-disc and the nucleus of cardiac myocytes
Protein kinase A, Ca2+/calmodulin-dependent kinase II, and calcineurin regulate the intracellular trafficking of myopodin between the Z-disc and the nucleus of cardiac myocytes
复制标题
DOI：
10.1128/mcb.00950-07
复制
发表时间：
2007-12-01
影响因子：
5.3
通讯作者：
Mundel, Peter
中科院分区：
文献类型：
--
作者：
Faul, Christian;Dhume, Ashwini;Mundel, Peter
细胞内信号传导的空间和时间分辨率可以通过区室化转导单元来实现。肌足蛋白是一种双室肌动蛋白捆绑蛋白，以分化和应激依赖的方式穿梭于肌细胞的细胞核和Z盘之间。肌足蛋白的输入蛋白α结合和核输入受肌足蛋白与14 - 3 - 3的丝氨酸/苏氨酸磷酸化依赖性结合的调节。在这里，我们表明，在心脏肌足蛋白形成一个Z盘信号复合物与α-辅肌动蛋白，钙调磷酸酶，钙/钙调蛋白依赖性激酶II（CaMKII），肌肉特异性A-激酶锚定蛋白，和myomegalin。通过蛋白激酶A（PKA）或CaMK II磷酸化肌足蛋白介导成肌细胞中14 - 3 - 3结合和核输入。钙调磷酸酶对肌足蛋白的去磷酸化消除了14 - 3 - 3 β结合。在成年心肌细胞中激活PKA或抑制钙调神经磷酸酶从Z盘释放肌足蛋白并诱导其核输入。肌足蛋白作为PKA、CaMKII和钙调神经磷酸酶的直接靶点的鉴定定义了一种新的细胞内信号传导途径，由此Z盘动力学的变化可以转化为心脏中的区室化信号转导。
Spatial and temporal resolution of intracellular signaling can be achieved by compartmentalizing transduction units. Myopodin is a dual-compartment, actin-bundling protein that shuttles between the nucleus and the Z-disc of myocytes in a differentiation- and stress-dependent fashion. Importin alpha binding and nuclear import of myopodin are regulated by serine/threonine phosphorylation-dependent binding of myopodin to 14-3-3. Here we show that in the heart myopodin forms a Z-disc signaling complex with alpha-actinin, calcineurin, Ca2+/calmodulin-dependent kinase II (CaMKII), muscle-specific A-kinase anchoring protein, and myomegalin. Phosphorylation of myopodin by protein kinase A (PKA) or CaMKII mediates 14-3-3 binding and nuclear import in myoblasts. Dephosphorylation of myopodin by calcineurin abrogates 14-3-3 beta binding. Activation of PKA or inhibition of calcineurin in adult cardiac myocytes releases myopodin from the Z-disc and induces its nuclear import. The identification of myopodin as a direct target of PKA, CaMKII, and calcineurin defines a novel intracellular signaling pathway whereby changes in Z-disc dynamics may translate into compartmentalized signal transduction in the heart.