Pezeshkpour Gholam H, Moatamed Farhad, Lewis Michael, Hoang Bao, Rettig Matthew, Mortazavi Fariborz
Department of Pathology, West Los Angeles VA, Los Angeles, CA, USA.
Genes Cancer. 2013 Jul;4(7-8):315-24. doi: 10.1177/1947601913497573.
CRK (c-Crk) as an adaptor protein is involved in several oncogenic signal transduction pathways, conveying oncogenic signals to its downstream effectors and thereby affecting multiple cellular processes including proliferation, differentiation, and migration. For example, we have observed that CRK expression and phosphorylation influence the invasiveness of non-small cell lung cancer (NSCLC) cells. To intervene in CRK signaling pathway, we examined whether CRK protein domains can be used as therapeutic tools to interrupt CRK signaling, thus influencing the biological behavior of NSCLC cells. For this purpose, Src Homology domains of CRK-I (i.e., SH2 and SH3N domains) were overexpressed in H157, Rh2, and A549 cells. CRK-SH3N domain expression induced epithelial morphology in H157 cells and enhanced epithelial morphology of A549 and Rh2 cells as compared to cells transfected with CRK-SH2 domain or empty vector. In addition, CRK-SH3N domain expression significantly decreased the motility and invasiveness of A549 and H157 cells. Furthermore, CRK-SH3N domain expression disrupted the interaction of CRK-II with DOCK180. In summary, these data provide evidence that the CRK-SH3N domain can be used to influence the malignant phenotype of NSCLC cells and also reduce the metastatic potential of these cells.
CRK（c-Crk）作为一种衔接蛋白，参与多种致癌信号转导途径，将致癌信号传递给其下游效应器，从而影响包括增殖、分化和迁移在内的多个细胞过程。例如，我们观察到CRK的表达和磷酸化会影响非小细胞肺癌（NSCLC）细胞的侵袭性。为了干预CRK信号通路，我们研究了CRK蛋白结构域是否可作为治疗工具来阻断CRK信号，从而影响NSCLC细胞的生物学行为。为此，在H157、Rh2和A549细胞中过表达了CRK-I的Src同源结构域（即SH2和SH3N结构域）。与转染CRK-SH2结构域或空载体的细胞相比，CRK-SH3N结构域的表达在H157细胞中诱导了上皮形态，并增强了A549和Rh2细胞的上皮形态。此外，CRK-SH3N结构域的表达显著降低了A549和H157细胞的运动性和侵袭性。此外，CRK-SH3N结构域的表达破坏了CRK-II与DOCK180的相互作用。总之，这些数据表明CRK-SH3N结构域可用于影响NSCLC细胞的恶性表型，并降低这些细胞的转移潜能。
