CD98hc (SLC3A2) mediates integrin signaling

Feral, Chloé C.; Nishiya, Naoyuki; Fenczik, Csilla A.; Stuhlmann, Heidi; Slepak, Marina; Ginsberg, Mark H.

doi:10.1073/pnas.0404852102

Cited by 232 publications

(277 citation statements)

References 33 publications

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“…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. Knockdown studies in human keratinocytes in vitro concluded the importance of CD98hc for cell adhesion and differentiation by regulating 1 integrin trafficking (Lemaître et al, 2011).…”

mentioning

confidence: 65%

“…CD98hc deletion in vitro impairs integrin-dependent functions, in particular as a result of a FAK phosphorylation defect (Feral et al, 2005(Feral et al, , 2007. We now show that CD98hc absence in the epidermis in vivo does not phenocopy adhesion Surprisingly, in 4OHT-treated K14-CreER T2 ; CD98hc fl/fl mice that displayed a major defect in wound healing, RhoA activity was persistently higher from days 3 to 7 after wounding, with no apparent regulation (Fig.…”

Section: Cd98hc-deficient Epidermis Displays a Strong In Vivo C-src Amentioning

confidence: 99%

“…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: 65%

Section: Cd98hc-deficient Epidermis Displays a Strong In Vivo C-src Amentioning

confidence: 99%

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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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“…[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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“…It is well documented from the work of others that 4F2 interacts with integrins and affects integrin pathways, altering the activation state of Akt and RacGTPase, leading to changes in cellular morphology, susceptibility to apoptosis and contributing to tumorigenesis. 29 The examination of these pathways and their potential link to exogenous LAT1 expression will be of interest.…”

Section: Discussionmentioning

confidence: 99%

Adenoviral modulation of the tumor‐associated system L amino acid transporter, LAT1, alters amino acid transport, cell growth and 4F2/CD98 expressionwith cell‐type specific effects in cultured hepatic cells

Storey

Fugère

Lesieur-Brooks

et al. 2005

Intl Journal of Cancer

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Altered expression of metabolite transporters is observed frequently in tumor cell lines and primary neoplasms. The extent to which these may to contribute to the growth autonomy associated with cancer is not clear. LAT1 is a major L-type amino acid transporter over-expressed in a variety of cancer types and a light chain component of the CD98 heterodimer. We utilized an adenoviral expression system to modulate the level of LAT1 in a hepatic in vitro model to examine phenotypic changes associated with short-term exogenous and blocked expression. LAT1 levels were increased three fold and resulted in increased L-type amino acid transport as a result of adenoviral expression in murine hepatocytes. The protein was expressed on the cell surface and complexed with the CD98 heavy chain known as 4F2. Surprisingly, levels of the total CD98 protein complex were increased 2.4-fold as a result of adenoviral expression of light chain only, suggesting coordinate regulation. Exogenous overexpression was less effective in normal rat liver cells relative to mouse. LAT1 antisense expression in hepatic tumor cells resulted in a modest though statistically significant decrease in cell number, viability and S-phase cells over a 5-day period relative to controls despite the absence of a significant decrease in L-type transport over this period. These studies are preparatory to in vivo efforts focusing on LAT1/CD98 as a potential therapeutic target. ' 2005 Wiley-Liss, Inc.Key words: LAT1; 4F2; CD98; leucine; adenovirus Recent studies have demonstrated that LAT1 is a major L-type amino acid transporter in a variety of cancer cells including hepatic, 1-3 oral, 4 breast, 5 bladder 6 and colon. 7 This predicted 12 transmembrane spanning protein mediates sodium independent transport of large neutral amino acids including several essential amino acids and is a major route for providing tumor cells with branched and aromatic amino acids. Because these amino acids are indispensable for growth and proliferation-dependent protein synthesis, LAT1 represents a target of high potential therapeutic interest. LAT1 exhibits broad substrate selectivity and is responsible for transport not only of naturally occurring amino acids, but also amino acid-related drugs such as l-dopa, melphalan, (an anti-cancer phenylalanine mustard), triiodothyronine and thyroxine and gabapentin, an anti-convulsant. Functional expression of LAT1 in the plasma membrane requires an additional single transmembrane glycoprotein known as 4F2 antigen or heavy chain and together these form a heterodimeric complex known as CD98. [8][9][10][11][12][13] The glycoprotein-associated transporters are a novel class of amino acid transporters recently the subject of much interest not only in relation to transport but also to CD98-linked functions in cell activation, integrin signaling, cell fusion and malignant transformation. [14][15][16][17] Our research has utilized a tetracycline-inducible adenoviral expression system (TET-Off) system to alter levels of LAT1 and 4F2 in vitro. We have...

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CD98hc (SLC3A2) mediates integrin signaling

Cited by 232 publications

References 33 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

Adenoviral modulation of the tumor‐associated system L amino acid transporter, LAT1, alters amino acid transport, cell growth and 4F2/CD98 expressionwith cell‐type specific effects in cultured hepatic cells

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