Cas and NEDD9 Contribute to Tumor Progression through Dynamic Regulation of the Cytoskeleton

Guerrero, Michael S.; Parsons, John T.; Bouton, Amy H.

doi:10.1177/1947601912458585

Cited by 40 publications

(46 citation statements)

References 96 publications

(217 reference statements)

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“…5B), further showing that reduced NEDD9 protein level by apigenin was through its post-translation modification. It has been reported that Akt together with other two scaffold proteins p130Cas and NEDD9 forms complex with FAK, Src, and Crk-L proteins (Guerrero et al, 2012). To investigate whether apigenin is able to inactivate FAK, Src, Crk-L, and Akt, phosphorylations of those proteins were examined.…”

Section: Resultsmentioning

confidence: 99%

“…Cas family proteins have no enzymatic activity but instead function as a platform for the assembly of multiprotein complexes, most notably Src and FAK, to influence cell behavior (Guerrero et al, 2012). Among Cas family members, NEDD9 and p130Cas are extensively studied and implicated in cell motility such as adhesion, cell migration, and invasion.…”

Section: Discussionmentioning

confidence: 99%

“…Among numerous binding partners of Cas and NEDD9, three proteins have been most consistently implicated in Cas/NEDD9 activity and signaling: Src, FAK, and the SH2 domain-containing adaptor molecule CrkL (Guerrero et al, 2012). The NEDD9/Src/FAK signaling complex plays an essential role in mediating movement toward growth factors and in translating mechanical forces into biochemical signals.…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of NEDD9 by apigenin suppresses migration, invasion, and metastasis of colorectal cancer cells

Dai

Wie

Fai

et al. 2016

Toxicology and Applied Pharmacology

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Apigenin is a natural flavonoid which possesses multiple anti-cancer properties such as anti-proliferation, anti-inflammation, and anti-metastasis in many types of cancers including colorectal cancer. Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is a multi-domain scaffolding protein of the Cas family which has been shown to correlate with cancer metastasis and progression. The present study investigates the role of NEDD9 in apigenin-inhibited cell migration, invasion, and metastasis of colorectal adenocarcinoma DLD1 and SW480 cells. The results show that knockdown of NEDD9 inhibited cell migration, invasion, and metastasis and that overexpression of NEDD9 promoted cell migration and invasion of DLD1 cells and SW4890 cells. Apigenin treatment attenuated NEDD9 expression at protein level, resulting in reduced phosphorylations of FAK, Src, and Akt, leading to inhibition on cell migration, invasion, and metastasis of both DLD1 and SW480 cells. The present study has demonstrated that apigenin inhibits cell migration, invasion, and metastasis through NEDD9/Src/Akt cascade in colorectal cancer cells. NEDD9 may function as a biomarker for evaluation of cancer aggressiveness and for selection of therapeutic drugs against cancer progression.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Downregulation of NEDD9 by apigenin suppresses migration, invasion, and metastasis of colorectal cancer cells

Dai

Wie

Fai

et al. 2016

Toxicology and Applied Pharmacology

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“…ABL-mediated tyrosine phosphorylation of NEDD9 and binding of C3G leads to activation of Rap1 and migration/chemotaxis of lymphoid cells [41]. The NEDD9/CRKL complex promotes actin polymerization and migration and chemotaxis through activation of WASP/ARP2/3 signaling (reviewed in [4, 54]).…”

Section: Altered Nedd9 Expression In Cancermentioning

confidence: 99%

Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

Shagisultanova

Gaponova

Gabbasov

et al. 2015

Gene

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Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases. Downstream, NEDD9 regulation of partners including CRKL, WAVE, PI3K/AKT, ERK, E-cadherin, Aurora-A (AURKA), HDAC6, and others allow NEDD9 to influence functions as pleiotropic as migration, invasion, survival, ciliary resorption, and mitosis. In this review, we summarize a growing body of preclinical and clinical data that indicate that while NEDD9 is itself non-oncogenic, changes in expression of NEDD9 (most commonly elevation of expression) are common features of tumors, and directly impact tumor aggressiveness, metastasis, and response to at least some targeted agents inhibiting NEDD9-interacting proteins. These data strongly support the relevance of further development of NEDD9 as a biomarker for therapeutic resistance. Finally, we briefly discuss emerging evidence supporting involvement of NEDD9 in additional pathological conditions, including stroke and polycystic kidney disease.

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“…NEDD9 plays important roles in cell migration and cell adhesion (reviewed in Bouton et al, 2001, Guerrero et al, 2012, can stabilize focal adhesions and induce cell spreading (Bradshaw et al, 2011, Baquiran et al, 2013, and has emerged as pro-metastasis factor in melanoma (Kim et al, 2006, Ahn et al, 2012, breast cancer (Izumchenko et al, 2009, Little et al, 2014, lung cancer (Miao et al, 2013, Kondo et al, 2012 and glioblastoma (Natarajan et al, 2006). This is the first study to establish a link between NRAGE and NEDD9 but it is interesting to note that other works have implicated NRAGE (Kumar et al, 2011) and NEDD9 (Kong et al, 2011, Ahn et al, 2012 in the negative regulation of E-cadherin-b-catenin and in EMT.…”

Section: Then Releases the P75ntrmentioning

confidence: 99%

p75NTR-dependent Rac1 activation requires receptor cleavage and activation of an NRAGE and NEDD9 signaling cascade

Zeinieh¹,

Salehi²,

Rajkumar³

et al. 2014

Journal of Cell Science

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The p75 neurotrophin receptor (p75NTR, also known as tumor necrosis factor receptor superfamily member 16) is implicated in diverse cellular events, but fundamental aspects of its signaling mechanisms remain unclear. To address this, we have established a novel bioassay to characterize signaling cascades activated by p75NTR. We show that in COS7 cells, p75NTR expression causes a large increase in cell surface area that relies on the activation of Rac1, and we demonstrate that the p75NTR-dependent COS7 phenotype is dependent on ADAM17-and c-secretase-dependent cleavage of p75NTR and generation of the p75NTR intracellular domain (p75NTR ICD ). We show that the p75NTR adaptor protein NRAGE (also known as MAGED1) acts downstream of the p75NTR ICD in this cascade and, through a yeast two-hybrid screen, identify NEDD9, a Cas family adaptor protein, as a novel NRAGE-binding partner that mediates p75NTR-dependent Rac1 activation and cell spreading. Our results demonstrate a crucial role for p75NTR cleavage in small GTPase activation and define a novel Rac1 activation pathway involving the p75NTR ICD , NRAGE and NEDD9.

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Cas and NEDD9 Contribute to Tumor Progression through Dynamic Regulation of the Cytoskeleton

Cited by 40 publications

References 96 publications

Downregulation of NEDD9 by apigenin suppresses migration, invasion, and metastasis of colorectal cancer cells

Downregulation of NEDD9 by apigenin suppresses migration, invasion, and metastasis of colorectal cancer cells

Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

p75NTR-dependent Rac1 activation requires receptor cleavage and activation of an NRAGE and NEDD9 signaling cascade

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