Grb2 regulation of the actin-based cytoskeleton is required for ligand-independent EGF receptor-mediated oncogenesis.
Grb2 regulation of the actin-based cytoskeleton is required for ligand-independent EGF receptor-mediated oncogenesis.
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Grb2 对基于肌动蛋白的细胞骨架的调节是配体独立的 EGF 受体介导的肿瘤发生所必需的。
DOI：
10.1038/sj.onc.1206830
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发表时间：
2003
期刊：
影响因子：
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通讯作者：
Maihle,NitaJ
中科院分区：
文献类型：
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作者：
Boerner,JulieL;Danielsen,AndrewJ;Lovejoy,CourtneyA;Wang,Ze;Juneja,SubhashC;Faupel-Badger,JessicaM;Darce,JaimeR;Maihle,NitaJ
EGF/ErbB受体家族成员内的突变经常释放这些受体的致癌潜力，导致独立于配体调控约束的下游信号传导事件的激活。我们以前已经证明，信号转导事件起源于S3-v-ErbB，配体独立的，致癌的EGF受体突变体，是定性不同的配体依赖性有丝分裂信号通路与野生型EGF受体。具体而言，S3-v-ErbB在原代成纤维细胞中的表达导致锚定非依赖性生长，增加的侵袭潜力，以及转化特异性磷蛋白信号传导复合物的形成，所有这些都以Ras非依赖性方式进行。在这里，我们证明了这个复杂的两个组件之间的转换特定的相互作用：衔接蛋白Grb 2和细胞骨架调节蛋白caldesmon。这种相互作用通过Grb 2的氨基末端SH 3和中央SH 2结构域以及钙调蛋白的氨基末端（肌球蛋白结合）结构域介导。在表达S3-v-ErbB的成纤维细胞中，缺乏羧基末端SH 3结构域的显性负性Grb 2缺失突变体的表达导致磷蛋白复合物形成减少、锚定非依赖性生长丧失和侵袭潜力降低。总之，这些结果证明了Ras独立的作用，Grb 2在调节细胞骨架功能，在配体非依赖性EGF受体介导的转化，并提供了进一步的支持的假设，即配体非依赖性致癌信号是定性不同的配体依赖性促有丝分裂信号的EGF受体。
Mutations within members of the EGF/ErbB receptor family frequently release the oncogenic potential of these receptors, resulting in the activation of downstream signaling events independent of ligand regulatory constraints. We previously have demonstrated that the signal transduction events originating from S3-v-ErbB, a ligand-independent, oncogenic EGF receptor mutant, are qualitatively distinct from the ligand-dependent mitogenic signaling pathways associated with the wild-type EGF receptor. Specifically, expression of S3-v-ErbB in primary fibroblasts results in anchorage-independent growth, increased invasive potential, and the formation of a transformation-specific phosphoprotein signaling complex, all in a Ras-independent manner. Here we demonstrate the transformation-specific interaction between two components of this complex: the adaptor protein Grb2 and the cytoskeletal regulatory protein caldesmon. This interaction is mediated via both the amino-terminal SH3 and central SH2 domains of Grb2, and the amino-terminal (myosin-binding) domain of caldesmon. Expression of a dominant-negative Grb2 deletion mutant, which lacks the carboxy-terminal SH3 domain, in fibroblasts expressing S3-v-ErbB results in a reduction in phosphoprotein complex formation, the loss of anchorage-independent growth, and a reduction in invasive potential. Together, these results demonstrate a Ras-independent role for Grb2 in modulating cytoskeletal function during ligand-independent EGF receptor-mediated transformation, and provide further support for the hypothesis that ligand-independent oncogenic signaling is qualitatively distinct from ligand-dependent mitogenic signaling by the EGF receptor.