Complementation of dominant suppression implicates CD98 in integrin activation

Fenczik, Csilla A.; Sethi, Tariq; Ramos, Joe W.; Hughes, Paul E.; Ginsberg, Mark H.

doi:10.1038/36349

Cited by 263 publications

(247 citation statements)

References 22 publications

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“…Expression of CD98hc in mammalian cells stimulates amino acid transport by promoting cell surface expression of the light chain (Mastroberardino et al, 1998). In addition to its role in amino acid transport, CD98hc interacts with integrins and regulates their signaling properties (Fenczik et al, 1997(Fenczik et al, , 2001Chandrasekaran et al, 1999;Zent et al, 2000;Kolesnikova et al, 2001;Merlin et al, 2001;Feral et al, 2005). Our studies and those of others have been instrumental in understanding how CD98hc physically and functionally interacts with integrins and regulates their functions in vitro (Merlin et al, 2001;Rintoul et al, 2002;Henderson et al, 2004;Feral et al, 2005Feral et al, , 2007.…”

mentioning

confidence: 69%

“…The transmembrane protein CD98hc participates in amino acid transport and integrin signaling by interacting, in particular, with 1A integrin (Fenczik et al, 1997;Merlin et al, 2001;Rintoul et al, 2002;Feral et al, 2005). CD98 is a heterodimer, in which a unique common heavy chain (4F2hc, CD98hc, SLC3A2) associates with one of several light chains composed of multiple membrane-spanning domains (Devés and Boyd, 2000).…”

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confidence: 99%

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CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

Boulter¹,

Estrach²,

Errante³

et al. 2013

J Cell Biol

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Skin aging is linked to reduced epidermal proliferation and general extracellular matrix atrophy. This involves factors such as the cell adhesion receptors integrins and amino acid transporters. CD98hc (SLC3A2), a heterodimeric amino acid transporter, modulates integrin signaling in vitro. We unravel CD98hc functions in vivo in skin. We report that CD98hc invalidation has no appreciable effect on cell adhesion, clearly showing that CD98hc disruption phenocopies neither CD98hc knockdown in cultured keratinocytes nor epidermal 1 integrin loss in vivo. Instead, we show that CD98hc deletion in murine epidermis results in improper skin homeostasis and epidermal wound healing. These defects resemble aged skin alterations and correlate with reduction of CD98hc expression observed in elderly mice. We also demonstrate that CD98hc absence in vivo induces defects as early as integrin-dependent Src activation. We decipher the molecular mechanisms involved in vivo by revealing a crucial role of the CD98hc/integrins/Rho guanine nucleotide exchange factor (GEF) leukemia-associated RhoGEF (LARG)/RhoA pathway in skin homeostasis. Finally, we demonstrate that the deregulation of RhoA activation in the absence of CD98hc is also a result of impaired CD98hc-dependent amino acid transports.

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confidence: 69%

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confidence: 99%

CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

Boulter¹,

Estrach²,

Errante³

et al. 2013

J Cell Biol

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“…We further show that the effect of CD98 overexpression on intestinal tumorigenesis in Apc Min/ þ mice could be explained by the fact that CD98 regulates cell proliferation and survival. Indeed, it has been shown that CD98 controls integrin signaling, which regulates cell proliferation, survival, migration, and epithelial adhesion/polarity, [1][2][3] and has crucial roles in intestinal homeostasis and tumorigenesis in mice. 8 In the present work, we observed that IEC-specific CD98 overexpression increased cell proliferation and reduced apoptosis in Apc Min/ þ mice, with both of these effects contributed to intestinal tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3] Expression of the transmembrane glycoprotein CD98, encoded by SLC3A2, is increased in various carcinomas. [4][5][6][7] Recently, we generated both gain-and loss-of-function mouse models featuring genetic manipulation of CD98 expression specifically in intestinal epithelial cells (IECs), and explored the roles of CD98 in intestinal homeostasis, inflammation, and colitis-associated tumorigenesis.…”

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confidence: 99%

Intestinal epithelial cell-specific CD98 expression regulates tumorigenesis in ApcMin/+ mice

Nguyen

Dalmasso

Yan

et al. 2012

Laboratory Investigation

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The transmembrane glycoprotein CD98 regulates integrin signaling that in turn controls cell proliferation and survival. CD98 expression is upregulated in various carcinomas, including colorectal cancer. Recently, by generating gain-and loss-of-function mouse models featuring genetic manipulation of CD98 expression specifically in intestinal epithelial cells (IECs), we have explored the crucial role of CD98 in the regulation of intestinal homeostasis and inflammation-associated tumorigenesis. In the present study, we investigated the contribution of CD98 to intestinal tumorigenesis in Apc Min/ þ mice and the underlying mechanism of action. Mice featuring IEC-specific CD98 overexpression (Tg animals) were crossed with Apc Min/ þ mice, and the characteristics of intestinal adenoma formation were assessed. Compared with Apc Min/ þ mice, Tg/Apc Min/ þ animals exhibited increases in both intestinal tumor incidence and tumor size; these parameters correlated with enhanced proliferation and decreased apoptosis of IECs. IEC-specific CD98 overexpression resulted in increased synthesis of the oncogenic proteins c-myc and cyclin-D1 in Apc Min/ þ mice, independently of the Wnt-APC-bcatenin pathway, suggesting the implication of CD98 overexpression-mediated Erk activation. IEC-specific CD98 overexpression enhanced the production of proinflammatory cytokines and chemokines that are crucial for tumorigenesis. We validated our results in mice exhibiting IEC-specific CD98 downregulation (CD98 flox/ þ VillinCre animals). IEC-specific CD98 downregulation efficiently attenuated tumor incidence and growth in Apc Min/ þ mice. The reduction of intestinal tumorigenesis upon IEC-specific CD98 downregulation was caused by the attenuation of IEC proliferation and cytokine/ chemokine production. In conclusion, we show that CD98 exerts an oncogenic activity in terms of intestinal tumorigenesis, via an ability to regulate tumor growth and survival.

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“…In addition, CD98 has been reported to participate in virus-mediated cell fusion (Ohgimoto et al, 1995) and regulation of integrin a nity (Fenczik et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Enhanced tumorigenicity caused by truncation of the extracellular domain of GP125/CD98 heavy chain

et al. 2000

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GP125/CD98 is a heterodimeric 125-kDa glycoprotein, which consists of an 85-kDa heavy chain (hc) and a 40-kDa light chain (lc), and is strongly expressed on the cell surface of various tumor cells, irrespective of their tissue of origin. We have recently demonstrated that overexpression of the CD98hc cDNA causes malignant transformation of NIH3T3 cells. To investigate the function of the extracellular domain of CD98hc in cell proliferation and malignant transformation, we established two NIH3T3-derived clones transfected with human truncated CD98hc cDNAs, and compared their characteristics with parental NIH3T3 and clones transfected with full-length CD98hc cDNA. Truncated as well as full-length CD98hc-transfected clones grew to a higher saturation density than control cells. E ciency of colony formation in soft agar was augmented in all CD98hc-transfected clones, and the degrees of augmented colony formation of the transfectants expressing fulllength CD98hc of 529 a.a. or truncated CD98hc of 418 a.a. were reduced by anti-human CD98hc antibodies, while that of the transfectant expressing truncated CD98hc of 237 a.a. lacking the epitopes recognized by anti-human CD98hc antibodies was not a ected by the addition of antibodies. CD98hc-transfected clones developed tumors in athymic mice, and tumor growth of truncated CD98hc-transfected clones was faster than that of full-length CD98hc-transfected clones. Oncogene (2000) 19, 6209 ± 6215.

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Complementation of dominant suppression implicates CD98 in integrin activation

Cited by 263 publications

References 22 publications

CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

Intestinal epithelial cell-specific CD98 expression regulates tumorigenesis in ApcMin/+ mice

Enhanced tumorigenicity caused by truncation of the extracellular domain of GP125/CD98 heavy chain

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