TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling

Jin, Wei; Cui, Yun; Mk, Kwak; Ta, Kim; Sj, Kim

doi:10.1038/sj.onc.1210571

Cited by 28 publications

(27 citation statements)

References 30 publications

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“…Along these lines, we also observed p130Cas expression to be up-regulated dramatically in the murine 4T1 model of mammary tumor progression (Fig. 1B) (26,27). Indeed, the highly metastatic 4T1 and 66c14 cells expressed significantly more p130Cas than did their moderately metastatic counterparts, 168-Farn and 4T07 (Fig.…”

Section: Elevated P130cas Expression Inhibits Tgf-␤-mediatedmentioning

confidence: 48%

p130Cas Is Required for Mammary Tumor Growth and Transforming Growth Factor-β-mediated Metastasis through Regulation of Smad2/3 Activity

Wendt

Smith

Schiemann

2009

Journal of Biological Chemistry

103

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During breast cancer progression, transforming growth factor-␤ (TGF-␤) switches from a tumor suppressor to a prometastatic molecule. Several recent studies suggest that this conversion in TGF-␤ function depends upon fundamental changes in the TGF-␤ signaling system. We show here that these changes in TGF-␤ signaling are concomitant with aberrant expression of the focal adhesion protein, p130Cas. Indeed, elevating expression of either the full-length (FL) or just the carboxyl terminus (CT) of p130Cas in mammary epithelial cells (MECs) diminished the ability of TGF-␤1 to activate Smad2/3, but increased its coupling to p38 MAPK. This shift in TGF-␤ signaling evoked (i) resistance to TGF-␤-induced growth arrest, and (ii) acinar filling upon three-dimensional organotypic cultures of p130Cas-FL or -CT expressing MECs. Furthermore, rendering metastatic MECs deficient in p130Cas enhanced TGF-␤-stimulated Smad2/3 activity, which restored TGF-␤-induced growth inhibition both in vitro and in mammary tumors produced in mice. Additionally, whereas elevating T␤R-II expression in metastatic MECs had no affect on their phosphorylation of Smad2/3, this event markedly enhanced their activation of p38 MAPK, leading to increased MEC invasion and metastasis. Importantly, depleting p130Cas expression in T␤R-II-expressing metastatic MECs significantly increased their activation of Smad2/3, which (i) reestablished the physiologic balance between canonical and noncanonical TGF-␤ signaling, and (ii) reversed cellular invasion and early mammary tumor cell dissemination stimulated by TGF-␤. Collectively, our findings identify p130Cas as a molecular rheostat that regulates the delicate balance between canonical and noncanonical TGF-␤ signaling, a balance that is critical to maintaining the tumor suppressor function of TGF-␤ during breast cancer progression.

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Section: Elevated P130cas Expression Inhibits Tgf-␤-mediatedmentioning

confidence: 48%

p130Cas Is Required for Mammary Tumor Growth and Transforming Growth Factor-β-mediated Metastasis through Regulation of Smad2/3 Activity

Wendt

Smith

Schiemann

2009

Journal of Biological Chemistry

103

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“…31,32 Importantly, both TrkC and ETV6-NTRK3 have been reported to bind to and inhibit TGFβRII, thereby negatively regulating SMAD phosphorylation and downstream TGFβ signaling. 35,36 To investigate whether TSPYL2 is required for RESTmediated TrkC repression, we first overexpressed TSPYL2 in A549 cells and found that TSPYL2 decreased TrkC mRNA and protein levels (Figures 4a and b). Interestingly, we also noticed that TrkC was induced by TGFβ in A549 cells, but that TSPYL2 completely abrogated this increase (Figure 4a and b).…”

Section: Resultsmentioning

confidence: 99%

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

et al. 2015

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REST/NRSF is a transcriptional repressor of neuronal genes that has been implicated in development and cancer. In epithelial tissues, REST acts as a tumor suppressor and in breast cancer, loss of REST is associated with disease recurrence and poor prognosis. Here, we identify TSPYL2 (also known as CDA1 and DENTT) as a novel component of the REST protein complex. We show that REST and TSPYL2 are regulators of TGFβ signaling and that cell-cycle arrest induced by TGFβ requires both REST and TSPYL2. Importantly, knockdown of REST or TSPYL2 resulted in transformation of human mammary epithelial cells. Mechanistically, we demonstrate that the TSPYL2/REST complex promotes TGFβ signaling by repressing the expression of genes, such as the proto-oncogene neurotrophic tyrosine kinase receptor C (TrkC). These data provide insight into the role of REST as a tumor suppressor in epithelial tissues through the regulation of the TGFβ pathway. Cell Death and Differentiation (2015) 22, 1353-1362 doi:10.1038/cdd.2014; published online 23 January 2015The transcription factor REST was originally discovered as a repressor of neuronal differentiation genes in non-neuronal lineages. Therefore, REST is considered as a master regulator of neurogenesis in development and maintenance of gene silencing. [1][2][3][4] Recently, it has been recognized that aberrant REST function also has a role in human malignancies, largely depending on the cellular context. 5 Focal genomic deletions targeting the REST locus have been found in colon adenocarcinoma and REST protein expression is often lost in small cell lung carcinoma cells. 6,7 In breast cancer, the loss of full-length (FL) REST protein is associated with disease recurrence and poor prognosis.8 However, the underlying mechanism of how REST protects against transformation in epithelial tissues has remained largely elusive.We have previously implicated the testis-specific protein, Y-encoded-like (TSPY-L) family of genes in cancer by identifying TSPYL5 expression as a prognostic marker of poor clinical outcome in breast cancer.9 TSPYL5 can interfere with p53-dependent cell-cycle arrest and oncogene-induced senescence triggering p53 ubiquitination and protein degradation.9 Besides TSPYL5, the TSPYL family of genes includes several other members (four coding genes and one pseudogene) whose functions are still unknown. All five proteins (TSPYL1, TSPYL2, TSPYL4, TSPYL5, and TSPYL6) are characterized by a predicted nucleosome assembly protein (NAP) domain, although functional evidence of NAP activity has not been reported of any of the TSPYL family members. TSPYL2, which shares only partial homology with TSPYL5, has been proposed as a candidate tumor suppressor in carcinoma cells.10 TSPYL2 is a negative regulator of proliferation, induces p21 CDKN1A , and inhibits anchorageindependent growth; however, the mechanism through which TSPYL2 may function as a tumor suppressor is poorly understood. [10][11][12] In this study, we identify TSPYL2 as a component of the REST/NRSF transcriptional repressor comple...

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“…Bambi, a T␤RI-related protein lacking a cytoplasmic kinase domain, acts as a pseudoreceptor by binding endogenous T␤RI and T␤RII, preventing receptor activation (65,66). TrkC, a member of the Trk family of neurotrophin receptors and Etv6-Ntrk3, a chimeric tyrosine kinase, bind to T␤RII and suppress T␤RII from activating T␤RI (67,68). A cholesterol-rich membrane microdomain marker caveolin-1 associates with T␤RI, leading to the internalization of T␤RI into caveolin-1 positive vesicles and its subsequent degradation via the proteasome pathway (69,70).…”

Section: Discussionmentioning

confidence: 99%

SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor

Liu

Nheu

Luwor

et al. 2015

Journal of Biological Chemistry

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Background: TGF-␤ signaling is tightly controlled by different regulators along its signaling cascade. Results: SPSB1 interacts and reduces the protein levels of T␤RII, which results in decreasing TGF-␤ signaling. Conclusion: SPSB1 acts as a new regulatory component of the TGF-␤ signaling pathway that targets T␤RII for degradation and provides fine control of its signaling. Significance: This is the first specific T␤RII negative regulator reported.

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TrkC binds to the type II TGF-β receptor to suppress TGF-β signaling

Cited by 28 publications

References 30 publications

p130Cas Is Required for Mammary Tumor Growth and Transforming Growth Factor-β-mediated Metastasis through Regulation of Smad2/3 Activity

p130Cas Is Required for Mammary Tumor Growth and Transforming Growth Factor-β-mediated Metastasis through Regulation of Smad2/3 Activity

TSPYL2 is an essential component of the REST/NRSF transcriptional complex for TGFβ signaling activation

SPSB1, a Novel Negative Regulator of the Transforming Growth Factor-β Signaling Pathway Targeting the Type II Receptor

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