Abstract
We have previously observed that tropomyosin receptor kinase B (TrkB) induces breast cancer metastasis by activating both the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and phosphatidylinositol-3-Kinase (PI3K)/AKT signaling pathways and inhibiting runt-related transcription factor 3 (RUNX3) and kelch-like ECH-associated protein 1 (KEAP1). These studies indicated that TrkB expression is crucial to the pathogenesis of breast cancer. However, how TrkB regulates bone morphogenetic protein (BMP) signaling and tumor suppression is largely unknown. Herein, we report that TrkB is a key regulator of BMP-mediated tumor suppression. TrkB enhances the metastatic potential of cancer cells by promoting cell anchorage-independent growth, migration, and suppressing BMP-2-mediated growth inhibition. TrkB inhibits the BMP-mediated activation of SMAD family member 1 (SMAD1) by promoting the formation of the TrkB/BMP type II receptor complex and suppresses RUNX3 by depleting BMP receptor I (BMPRI) expression. In addition, the knockdown of TrkB restored the tumor-inhibitory effect of BMP-2 via the activation of SMAD1. Moreover, the TrkB kinase activity was required for its effect on BMP signaling. Our study identified a unique role of TrkB in the regulation of BMP-mediated growth inhibition and BMP-2-induced RUNX3 expression.
Highlights
The bone morphogenetic protein (BMP) family, a member of the transforming growth factor-β (TGF-β) superfamily, consists of over 20 multifunctional growth factors with a broad range of regulatory functions, including embryonic development, apoptosis, chemotaxis, proliferation, and differentiation [1,2,3,4]
We have previously demonstrated that tropomyosin receptor kinase B (TrkB) induces breast cancer metastasis by activating the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) and phosphatidylinositol-3-Kinase (PI3K)/AKT signaling pathways [25], and suppressing runt-related transcription factor 3 (RUNX3) and kelch-like ECH-associated protein 1 (KEAP1)
To understand the correlation between TrkB and BMP signaling, we examined whether TrkB
Summary
The bone morphogenetic protein (BMP) family, a member of the transforming growth factor-β (TGF-β) superfamily, consists of over 20 multifunctional growth factors with a broad range of regulatory functions, including embryonic development, apoptosis, chemotaxis, proliferation, and differentiation [1,2,3,4]. As part of the TGF-β signaling pathway, BMP-2 is secreted when the BMP receptor type I (BMPRIA) and II (BMPRII) complexes on the cell surface, which leads to the activation, and nuclear translocation of SMAD family member 1 (SMAD1), in association with SMAD4, to regulate specific target gene expression [5,6,7]. Similar to the functions of TGF-β in the cancer microenvironments, BMPs, and their receptors play a dual tumor-suppressive and -promoting role in cancer. Gremlin 1 was found to be responsible for the tumorigenic potential of cancer cells by inhibiting BMP/SMAD signaling, and its expression was associated with poor prognosis in breast cancer patients [9].
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