FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth
FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth
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DOI：
10.1093/emboj/cdf631
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发表时间：
2002-12-02
期刊：
影响因子：
11.4
通讯作者：
Schlaepfer, DD
中科院分区：
文献类型：
--
作者：
Hauck, CR;Hsia, DA;Schlaepfer, DD
粘着斑激酶（FAK）首先被鉴定为病毒Src（v-Src）底物，但FAK在Src转化事件中的作用仍然不确定。我们发现，FAK C-末端结构域（称为FRNK）在v-Src转化的NIH 3 T3成纤维细胞中的稳定表达通过Matrigel抑制细胞侵袭，并阻断裸鼠实验转移，而不影响细胞运动。FRNK抑制活性依赖于其局部接触定位。FRNK表达破坏了v-Src-FAK信号复合物的形成，抑制p130 Cas酪氨酸磷酸化，并减弱v-Src刺激的ERK和JNK激酶活化。然而，FRNK不影响v-Src刺激的Akt激活，软琼脂中的细胞生长或裸鼠皮下肿瘤形成。表达FRNK的细胞表现出降低的基质金属蛋白酶-2（MMP-2）mRNA水平和MMP-2分泌。在人293细胞中的瞬时FRNK表达抑制了外源性MMP-2启动子活性，并且在FRNK存在下，野生型MMP-2的过表达（但不是催化失活的（Ala-404）MMP-2）拯救了v-Src刺激的基质胶侵袭。我们的研究结果显示FAK在Src刺激的细胞侵袭中的重要性，并支持Src-FAK信号传导与肿瘤细胞转移升高相关的作用。
Focal adhesion kinase (FAK) was first identified as a viral Src (v-Src) substrate, but the role of FAK in Src transformation events remains undefined. We show that stable expression of the FAK C-terminal domain (termed FRNK) in v-Src-transformed NIH 3T3 fibroblasts inhibited cell invasion through Matrigel and blocked experimental metastases in nude mice without effects on cell motility. FRNK inhibitory activity was dependent upon its focal contact localization. FRNK expression disrupted the formation of a v-Src-FAK signaling complex, inhibited p130Cas tyrosine phosphorylation, and attenuated v-Src-stimulated ERK and JNK kinase activation. However, FRNK did not affect v-Src-stimulated Akt activation, cell growth in soft agar, or subcutaneous tumor formation in nude mice. FRNK-expressing cells exhibited decreased matrix metalloproteinase-2 (MMP-2) mRNA levels and MMP-2 secretion. Transient FRNK expression in human 293 cells inhibited exogenous MMP-2 promoter activity and overexpression of wild-type but not catalytically-inactive (Ala-404) MMP-2 rescued v-Src-stimulated Matrigel invasion in the presence of FRNK. Our findings show the importance of FAK in Src-stimulated cell invasion and support a role for Src-FAK signaling associated with elevated tumor cell metastases.