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Brk Activates Rac1 and Promotes Cell Migration and Invasion by Phosphorylating Paxillin

机译：Brk通过磷酸化Paxillin激活Rac1并促进细胞迁移和侵袭

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摘要

Brk (for breast tumor kinase) is a nonreceptor tyrosine kinase containing SH3, SH2, and tyrosine kinase catalytic domains. Brk was originally identified from a human metastatic breast tumor, and its overexpression is frequently observed in breast cancer and several other cancer types. However, the molecular mechanism by which this kinase participates in tumorigenesis remains poorly characterized. In the present study, we not only identified paxillin as the binding partner and substrate of Brk but also discovered a novel signaling pathway by which Brk mediates epidermal growth factor (EGF)-induced paxillin phosphorylation. We show that EGF stimulation activates the catalytic activity of Brk, which in turn phosphorylates paxillin at Y31 and Y118. These phosphorylation events promote the activation of small GTPase Rac1 via the function of CrkII. Through this pathway, Brk is capable of promoting cell motility and invasion and functions as a mediator of EGF-induced migration and invasion. In accordance with these functional roles, Brk translocates to membrane ruffles, where it colocalizes with paxillin during cell migration. Together, our findings identify novel signaling and biological roles of Brk and indicate the first potential link between Brk and metastatic malignancy.
机译：Brk（用于乳腺肿瘤激酶）是一种非受体酪氨酸激酶，包含SH3，SH2和酪氨酸激酶催化域。 Brk最初是从人类转移性乳腺肿瘤中鉴定出来的，在乳腺癌和其他几种癌症类型中经常观察到Brk的过度表达。但是，该激酶参与肿瘤发生的分子机制仍然很差。在本研究中，我们不仅确定了Paxillin作为Brk的结合伴侣和底物，还发现了Brk介导表皮生长因子（EGF）诱导的Paxillin磷酸化的新型信号途径。我们表明，EGF刺激激活Brk的催化活性，而Brk则在Y31和Y118磷酸化Paxillin。这些磷酸化事件通过CrkII的功能促进了小GTPase Rac1的激活。通过这一途径，Brk能够促进细胞运动和侵袭，并作为EGF诱导的迁移和侵袭的介质。根据这些功能性作用，Brk易位至膜褶皱，在细胞迁移过程中它与Paxillin共定位。总之，我们的发现确定了Brk的新型信号传导和生物学作用，并表明Brk与转移性恶性肿瘤之间的第一个潜在联系。

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