RhoA Signaling in Transformation by v-Src

描述（由申请人提供）：本提案的长期目标是了解RhoA在v-Src转化中的作用，RhoA是一种诱导肌动蛋白应激纤维的小GTPase。在细胞中，v-Src是c-Src酪氨酸激酶的一种活化形式，被认为通过持续刺激正常瞬时信号通路来促进转化。事实上，某些人类癌症具有升高的c-Src活性，并且肿瘤进展与Src活性水平相关。几项研究表明，v-Src降低RhoA[GTP]水平，这导致转化细胞中的肌动蛋白应激纤维损失。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand the role of RhoA, a small GTPase that induces actin stress fibers, in v-Src transformation. In cells, v-Src, an activated form of the c-Src tyrosine kinase, is thought to promote transformation by continually stimulating normally transient signaling pathways. In fact, certain human cancers have elevated c-Src activity, and tumor progression correlates with the Src activity level. Several studies suggest that v-Src decreases RhoA[GTP] levels, and that this causes actin stress fiber loss in transformed cells. However, evidence from our laboratory indicates v-Src activity enhances RhoA[GTP] levels. RhoA is also required for the proliferation of non-transformed cells, likely by regulating the timing of expression of key cell cycle regulators and sustaining MAPK activity during cell cycle progression. These observations have led to the following general hypothesis: v-Src induced mitogenic transformation requires RhoA signaling, but v-Src induced actin stress fiber disassembly and cell motility, circumvent RhoA signaling. Three Specific Aims will test this hypothesis: 1) Investigate the requirement for RhoA signaling in v-Src-mediated mitogenic transformation. 2) Determine the mechanism by which v-Src induces cofilin activation. 3) Evaluate the significance of cofilin activation on cell migration and invasion in cells with elevated Src kinase activity.