Orian-Rousseau Véronique, Chen Linfeng, Sleeman Jonathan P, Herrlich Peter, Ponta Helmut
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, D-76021 Karlsruhe, Germany.
Genes Dev. 2002 Dec 1;16(23):3074-86. doi: 10.1101/gad.242602.
The tyrosine kinase receptor c-Met and its ligand HGF/SF, ezrin, and splice variants of CD44 have independently been identified as tumor metastasis-associated proteins. We now show that these proteins cooperate. A CD44 isoform containing variant exon v6 sequences is strictly required for c-Met activation by HGF/SF in rat and human carcinoma cells, in established cell lines as well as in primary keratinocytes. CD44v6-deficient tumor cells were unable to activate c-Met unless they were transfected with a CD44v6-bearing isoform. Antibodies to two v6-encoded epitopes inhibited autophosphorylation of c-Met by interfering with the formation of a complex formed by c-Met, CD44v6, and HGF/SF. In addition, signal transduction from activated c-Met to MEK and Erk required the presence of the cytoplasmic tail of CD44 including a binding motif for ERM proteins. This suggests a role for ERM proteins and possibly their link to the cortical actin cytoskeleton in signal transfer.
酪氨酸激酶受体c-Met及其配体HGF/SF、埃兹蛋白和CD44的剪接变体已分别被鉴定为肿瘤转移相关蛋白。我们现在发现这些蛋白相互协作。在大鼠和人类癌细胞、已建立的细胞系以及原代角质形成细胞中，含有可变外显子v6序列的CD44同种型对于HGF/SF激活c-Met是严格必需的。缺乏CD44v6的肿瘤细胞无法激活c-Met，除非它们被转染了携带CD44v6的同种型。针对两个v6编码表位的抗体通过干扰由c-Met、CD44v6和HGF/SF形成的复合物的形成来抑制c-Met的自磷酸化。此外，从激活的c-Met到MEK和Erk的信号转导需要CD44的细胞质尾巴的存在，包括一个与ERM蛋白的结合基序。这表明ERM蛋白可能在信号传递中发挥作用，并且可能与皮质肌动蛋白细胞骨架存在联系。
