CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling

Abstract

Casitas B-lineage lymphoma (CBL) protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types. Recent discovery revealed mutations of proto-oncogenic CBL in the linker region and RING finger domain in human acute myeloid neoplasm, and these transforming mutations induced carcinogenesis. However, the adaptor function of CBL mediated signaling pathway during tumorigenesis has not been well characterized. Here, we show that CBL is highly expressed in breast cancer cells and significantly inhibits transforming growth factor-b (TGF-b) tumor suppressive activity. Knockdown of CBL expression resulted in the increased expression of TGF-b target genes, PAI-I and CDK inhibitors such as p15 INK4b and p21 Cip1 . Furthermore, we demonstrate that CBL is frequently overexpressed in human breast cancer tissues, and the loss of CBL decreases the tumorigenic activity of breast cancer cells in vivo. CBL directly binds to Smad3 through its proline-rich motif, thereby preventing Smad3 from interacting with Smad4 and blocking nuclear translocation of Smad3. CBL-b, one of CBL protein family, also interacted with Smad3 and knockdown of both CBL and CBL-b further enhanced TGF-b transcriptional activity. Our findings provide evidence for a previously undescribed mechanism by which oncogenic CBL can block TGF-b tumor suppressor activity.

YC‐1 inhibits proliferation of breast cancer cells by down‐regulating EZH2 expression via activation of c‐Cbl and ERK

“…Additionally, YC-1 induced EGFR degradation in a proteasome-dependent manner, and the depletion of c-Cbl attenuated YC-1-induced EGFR inhibition (data not shown), which indicated that YC-1 also mediated c-Cbl to promote EGFR degradation. c-Cbl functions as a proto-oncogene, which is related to tumourigenesis in breast cancer (Kang et al, 2012). The YC-1-induced c-Cbl suppression may also contribute to antitumour activity in MDA-MB-468 cells.…”

Phospho-specific Smad3 signaling

“…This occurs through direct binding with Smad3 and not Smad2 in a C-terminal phosphorylation-dependent manner, preventing Smad3 from forming a complex with Smad4. 65 Recently, the transcriptional co-regulator SKI was found to promote linker phosphorylation of Smad3 and TGFβ-induced oncogenesis in melanoma cells. 66 In invasive breast cancer tissue samples, increased cytoplasmic SKI expression is inversely associated with tumor size, stage and lymph node status and positively associated with longer disease-free survival.…”

KIAA1324 Suppresses Gastric Cancer Progression by Inhibiting the Oncoprotein GRP78

“…SNU16 cell lines stably expressing control or KIAA1324 shRNA were generated as described previously (25). To establish MKN28 and AGS cell lines expressing KIAA1324 in a doxycycline-dependent manner (tet-on), the human KIAA1324 gene was cloned into pCMV-3HA vector (Clontech).…”