Xu Yichen, Zhang Hua, Lit Lei C, Grothey Arnhild, Athanasiadou Maria, Kiritsi Marianna, Lombardo Ylenia, Frampton Adam E, Green Andrew R, Ellis Ian O, Ali Simak, Lenz Heinz-Josef, Thanou Maya, Stebbing Justin, Giamas Georgios
Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK.
Department of Surgery and Cancer, Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, UK. Department of Physiology, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Sci Signal. 2014 Jun 17;7(330):ra58. doi: 10.1126/scisignal.2005170.
Lemur tyrosine kinase 3 (LMTK3) is associated with cell proliferation and endocrine resistance in breast cancer. We found that, in cultured breast cancer cell lines, LMTK3 promotes the development of a metastatic phenotype by inducing the expression of genes encoding integrin subunits. Invasive behavior in various breast cancer cell lines positively correlated with the abundance of LMTK3. Overexpression of LMTK3 in a breast cancer cell line with low endogenous LMTK3 abundance promoted actin cytoskeleton remodeling, focal adhesion formation, and adhesion to collagen and fibronectin in culture. Using SILAC (stable isotope labeling by amino acids in cell culture) proteomic analysis, we found that LMTK3 increased the abundance of integrin subunits α5 and β1, encoded by ITGA5 and ITGB1. This effect depended on the CDC42 Rho family guanosine triphosphatase, which was in turn activated by the interaction between LMTK3 and growth factor receptor-bound protein 2 (GRB2), an adaptor protein that mediates receptor tyrosine kinase-induced activation of RAS and downstream signaling. Knockdown of GRB2 suppressed LMTK3-induced CDC42 activation, blocked ITGA5 and ITGB1 expression promoted by the transcription factor serum response factor (SRF), and reduced invasive activity. Furthermore, abundance of LMTK3 positively correlated with that of the integrin β1 subunit in breast cancer patient's tumors. Our findings suggest a role for LMTK3 in promoting integrin activity during breast cancer progression and metastasis.
狐猴酪氨酸激酶3（LMTK3）与乳腺癌的细胞增殖和内分泌抵抗相关。我们发现，在培养的乳腺癌细胞系中，LMTK3通过诱导编码整合素亚基的基因表达来促进转移表型的形成。多种乳腺癌细胞系中的侵袭行为与LMTK3的丰度呈正相关。在低内源性LMTK3丰度的乳腺癌细胞系中过表达LMTK3可促进肌动蛋白细胞骨架重塑、粘着斑形成以及在培养中对胶原蛋白和纤连蛋白的粘附。使用SILAC（细胞培养中氨基酸稳定同位素标记）蛋白质组学分析，我们发现LMTK3增加了由ITGA5和ITGB1编码的整合素亚基α5和β1的丰度。这种效应依赖于CDC42 Rho家族鸟苷三磷酸酶，而该酶又通过LMTK3与生长因子受体结合蛋白2（GRB2）之间的相互作用被激活，GRB2是一种衔接蛋白，介导受体酪氨酸激酶诱导的RAS激活和下游信号传导。敲低GRB2可抑制LMTK3诱导的CDC42激活，阻断转录因子血清反应因子（SRF）促进的ITGA5和ITGB1表达，并降低侵袭活性。此外，LMTK3的丰度与乳腺癌患者肿瘤中整合素β1亚基的丰度呈正相关。我们的研究结果表明LMTK3在乳腺癌进展和转移过程中促进整合素活性方面发挥作用。
