Abstract
The acquisition of inappropriate migratory feature is crucial for tumor metastasis. It has been suggested that CD147 and Annexin A2 are involved in regulating tumor cell movement, while the regulatory mechanisms are far from clear. In this study, we demonstrated that CD147 physically interacted with the N-terminal domain of Annexin A2 and decreased Annexin A2 phosphorylation on tyrosine 23. In vitro kinase assay showed that the I domain of CD147 was indispensable for CD147-mediated downregulation of Annexin A2 phosphorylation by Src. Furthermore, we determined that p-Annexin A2 promoted the expression of dedicator of cytokinesis 3 (DOCK3) and DOCK3 blocked β-catenin nuclear translocation, resulting in inhibition of β-catenin signaling. In addition, DOCK3 inhibited lamellipodium dynamics and tumor cell movement. Also, we found that β-catenin signaling increased WAVE2 expression. Therefore, DOCK3 was characterized as a negative regulator of WAVE2 expression via inhibiting β-catenin signaling. Our study provides the first evidence that CD147 promotes tumor cell movement and metastasis via direct interaction with Annexin A2 and DOCK3-β-catenin-WAVE2 signaling axis.
Highlights
The majority of deaths associated with cancer are due to the metastasis of the original tumor cells [1]
We previously performed co-localization assay using ER-Tracker to indicate ER location and we found that Annexin A2 Y23F co-localized with CD147 in cytoplasm closed to ER [5]
We have shown that CD147 inhibits Annexin A2 phosphorylation and Annexin A2 phosphorylation induces dedicator of cytokinesis 3 (DOCK3) expression, we supposed that CD147 could inhibit DOCK3 expression and promote cell movement via interacting with Annexin A2
Summary
The majority of deaths associated with cancer are due to the metastasis of the original tumor cells [1]. Metastasis is an exceedingly complex and multi-step process. The acquisition of inappropriate migratory and invasive characteristics is a common feature of metastatic cancer cells. Rho family GTPases are intracellular signaling molecules that play critical roles in regulating cytoskeleton reorganization and cell movement [2]. The activities of most Rho family members depend on a delicate balance between the GTP-bound, active state and the GDP-bound, inactive state. The cycling between these two states is positively controlled by guanine nucleotide exchange factors (GEFs)
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