The Integrin-coupled Signaling Adaptor p130Cas Suppresses Smad3 Function in Transforming Growth Factor-β Signaling

Kim, Wook; Kang, Young-Min; Kim, Jin-Soo; Shin, Nah-Young; Hanks, Steven K.; Song, Woo Keun

doi:10.1091/mbc.e07-10-0991

Cited by 50 publications

(49 citation statements)

References 41 publications

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“…In this context p130CAS has been shown to be a crucial player by binding to SMAD3, and preventing its phosphorylation by TGF receptor. As a consequence, the transcription of the cyclin-dependent kinase inhibitors p15 and p21 is inhibited, resulting in cell cycle progression 72 . Recently, it has been reported that p130CAS over-expression in mammary epithelial cells (MECs) shifts TGF signalling from SMAD2/SMAD3 phosphorylation to p38 MAPK activation, rendering MECs resistant to TGF-induced growth arrest and enhancing their metastatic potential 73 .…”

Section: Migration and Invasionmentioning

confidence: 99%

Integrin signalling adaptors: not only figurants in the cancer story

et al. 2010

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Current evidence highlights the ability of adaptor (or scaffold) proteins to create signalling platforms that drive cellular transformation upon integrin-dependent adhesion and growth factor receptor activation. The understanding of the biological effects regulated by these adaptors in tumours might be crucial for the identification of novel targets and the development of innovative therapeutic strategies for human cancer. In this review we will discuss the relevance of adaptor proteins in signalling originating from integrin-mediated cell-extracellular matrix (ECM) adhesion and growth factor stimulation within the context of cell transformation and tumour progression.Herein, we will specifically underline the contribution of p130CAS, NEDD9, CRK, and the IPP complex (ILK, PINCH and PARVIN) to cancer, along with the more recently identified p140CAP.

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Section: Migration and Invasionmentioning

confidence: 99%

Integrin signalling adaptors: not only figurants in the cancer story

et al. 2010

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“…Representative acini are shown. (21). Unfortunately, the pathophysiological importance of these events, if any, in mediating oncogenic TGF-␤ signaling in normal and malignant MECs remains unknown.…”

Section: Elevated P130cas Expression Inhibits Tgf-␤-mediatedmentioning

confidence: 99%

“…Collectively, these findings highlight the critical roles played by p130Cas in regulating normal tissue morphogenesis, and in promoting breast cancer progression. With respect to TGF-␤, a recent study identified p130Cas as a potential inhibitor of Smad3 function (21). However, the pathophysiological importance of this event, if any, in mediating the oncogenic activities of TGF-␤ and/or p130Cas during breast cancer progression remains to be established.…”

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confidence: 99%

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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“…3,4 Tight regulation of p130Cas function via proteolytic cleavage or reversible phosphorylation of tyrosine residues is necessary for the maintenance of cell motility, survival, and apoptosis in various cell types. [5][6][7][8] Although high expression of p130Cas in primary breast tumors is linked to activation of cell proliferation and cancer progression, the detailed mechanisms governing p130Cas expression are not fully understood.…”

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confidence: 99%

Downregulation of microRNA-362-3p and microRNA-329 promotes tumor progression in human breast cancer

Kang

et al. 2015

Cell Death Differ

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p130Cas regulates cancer progression by driving tyrosine receptor kinase signaling. Tight regulation of p130Cas expression is necessary for survival, apoptosis, and maintenance of cell motility in various cell types. Several studies revealed that transcriptional and post-translational control of p130Cas are important for maintenance of its expression and activity. To explore novel regulatory mechanisms of p130Cas expression, we studied the effect of microRNAs (miRs) on p130Cas expression in human breast cancer MCF7 cells. Here, we provide experimental evidence that miR-362-3p and miR-329 perform a tumor-suppressive function and their expression is downregulated in human breast cancer. miR-362-3p and miR-329 inhibited cellular proliferation, migration, and invasion, thereby suppressing tumor growth, by downregulating p130Cas. Ectopic expression of p130Cas attenuated the inhibitory effects of the two miRs on tumor progression. Relative expression levels of miR-362-3p/329 and p130Cas between normal and breast cancer correlated inversely; miR-362-3p/329 expression was decreased, whereas that of p130Cas increased in breast cancers. Furthermore, we showed that downregulation of miR-362-3p and miR-329 was caused by differential DNA methylation of miR genes. Enhanced DNA methylation (according to methylation-specific PCR) was responsible for downregulation of miR-362-3p and miR-329 in breast cancer. Taken together, these findings point to a novel role for miR-362-3p and miR-329 as tumor suppressors; the miR-362-3p/miR-329-p130Cas axis seemingly has a crucial role in breast cancer progression. Thus, modulation of miR-362-3p/miR-329 may be a novel therapeutic strategy against breast cancer. Cell Death and Differentiation (2016) 23, 484-495; doi:10.1038/cdd.2015; published online 4 September 2015 p130Cas/breast cancer anti-estrogen resistance 1 is a member of the Cas (Crk-associated substrate) family of adaptor proteins and has a central role in tyrosine kinasebased signaling related to cell adhesion, migration, cell cycle control, apoptosis, development, and cancer progression.

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The Integrin-coupled Signaling Adaptor p130Cas Suppresses Smad3 Function in Transforming Growth Factor-β Signaling

Cited by 50 publications

References 41 publications

Integrin signalling adaptors: not only figurants in the cancer story

Integrin signalling adaptors: not only figurants in the cancer story

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

Downregulation of microRNA-362-3p and microRNA-329 promotes tumor progression in human breast cancer

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