Role of the fungal Ras-protein kinase A pathway in governing epithelial cell interactions during oropharyngeal candidiasis

Park, Hyun‐Sook; Myers, Carter L.; Sheppard, Donald C.; Phan, Quynh T.; Sanchez, Angela A.; Edwards, John E.; Filler, Scott G.

doi:10.1111/j.1462-5822.2004.00476.x

Cited by 189 publications

(310 citation statements)

References 56 publications

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“…The animal studies were approved by the Animal Care and Use Committee at the Los Angeles Biomedical Research Institute. The effect of GW2974 on the severity of OPC was determined using a minor modification of our standard mouse model (34,35). Male BALB/C mice were fed either powdered mouse chow or chow containing 200 μg GW2974 per 1 g starting on day −2 relative to infection (17).…”

Section: Methodsmentioning

confidence: 99%

EGFR and HER2 receptor kinase signaling mediate epithelial cell invasion by Candida albicans during oropharyngeal infection

Zhu

Phan

Boontheung

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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162

191

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The fungus Candida albicans is the major cause of oropharyngeal candidiasis (OPC). A key feature of this disease is fungal invasion of oral epithelial cells, a process that can occur by active penetration and fungal-induced endocytosis. Two invasins, Als3 and Ssa1, induce epithelial cell endocytosis of C. albicans, in part by binding to E-cadherin. However, inhibition of E-cadherin function only partially reduces C. albicans endocytosis, suggesting that there are additional epithelial cell receptors for this organism. Here, we show that the EGF receptor (EGFR) and HER2 function cooperatively to induce the endocytosis of C. albicans hyphae. EGFR and HER2 interact with C. albicans in an Als3-and Ssa1-dependent manner, and this interaction induces receptor autophosphorylation. Signaling through both EGFR and HER2 is required for maximal epithelial cell endocytosis of C. albicans in vitro. Importantly, oral infection with C. albicans stimulates the phosphorylation of EGFR and HER2 in the oral mucosa of mice, and treatment with a dual EGFR and HER2 kinase inhibitor significantly decreases this phosphorylation and reduces the severity of OPC. These results show the importance of EGFR and HER2 signaling in the pathogenesis of OPC and indicate the feasibility of treating candidal infections by targeting the host cell receptors with which the fungus interacts.

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Section: Methodsmentioning

confidence: 99%

EGFR and HER2 receptor kinase signaling mediate epithelial cell invasion by Candida albicans during oropharyngeal infection

Zhu

Phan

Boontheung

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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162

191

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“…To create prototrophic versions of the dac1⌬/dac1⌬ and nag1⌬/nag1⌬ mutants, they were transformed with a URA3-containing DNA fragment to restore URA3 at its native locus. The URA3 frag- ments were liberated from plasmid pBSK-URA3 (20) by digestion with restriction enzymes PstI and NotI.…”

Section: Methodsmentioning

confidence: 99%

N-Acetylglucosamine (GlcNAc) Induction of Hyphal Morphogenesis and Transcriptional Responses in Candida albicans Are Not Dependent on Its Metabolism

Naseem¹,

Gunasekera²,

Araya

et al. 2011

Journal of Biological Chemistry

118

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N-Acetylglucosamine (GlcNAc) stimulates important signaling pathways in a wide range of organisms. In the human fungal pathogen Candida albicans, GlcNAc stimulates hyphal cell morphogenesis, virulence genes, and the genes needed to catabolize GlcNAc. Previous studies on the GlcNAc transporter (NGT1) indicated that GlcNAc has to be internalized to induce signaling. Therefore, the role of GlcNAc catabolism was examined by deleting the genes required to phosphorylate, deacetylate, and deaminate GlcNAc to convert it to fructose-6-PO 4 (HXK1, NAG1, and DAC1). As expected, the mutants failed to utilize GlcNAc. Surprisingly, GlcNAc inhibited the growth of the nag1⌬ and dac1⌬ mutants in the presence of other sugars, suggesting that excess GlcNAc-6-PO 4 is deleterious. Interestingly, both hxk1⌬ and an hxk1⌬ nag1⌬ dac1⌬ triple mutant could be efficiently stimulated by GlcNAc to form hyphae. These mutants could also be stimulated to express GlcNAcregulated genes. Because GlcNAc must be phosphorylated by Hxk1 to be catabolized, and also for it to enter the anabolic pathways that form chitin, N-linked glycosylation, and glycosylphosphatidylinositol anchors, the mutant phenotypes indicate that GlcNAc metabolism is not needed to induce signaling in C. albicans. Thus, these studies in C. albicans reveal a novel role for GlcNAc in cell signaling that may also regulate critical pathways in other organisms.

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“…As a result, hyphal-deficient mutants do not express these invasins, and are therefore defective in both induced endocytosis and active penetration. This defect in two different host cell invasion mechanisms is the likely explanation for the profound virulence attenuation of the hyphal-deficient C. albicans mutant that lacks the Efg1 transcription factor (Park et al 2005). On the other hand, although the als3D/D mutant forms normal length hyphae, it is defective in both induced endocytosis and active penetration in vitro (Phan et al 2007;Wachtler et al 2012).…”

mentioning

confidence: 99%

“…albicans can invade epithelial cells by two different mechanisms: induced endocytosis and active penetration (Park et al 2005;Zakikhany et al 2007;Dalle et al 2010;Zhu and Filler 2010;Wachtler et al 2012). In addition, C. albicans can invade epithelial cell barriers by a paracellular route that involves the proteolytic digestion of tight junctions (Frank and Hostetter 2007;Villar et al 2007;Rollenhagen et al 2009).…”

mentioning

confidence: 99%

Host Cell Invasion by Medically Important Fungi

Sheppard

Filler

2014

Cold Spring Harbor Perspectives in Medicine

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Role of the fungal Ras-protein kinase A pathway in governing epithelial cell interactions during oropharyngeal candidiasis

Abstract: Summary Tpk1p, Tpk2p and Efg1p are members of the Rasprotein kinase A pathway that governs the yeast-tohyphal transition in Candida albicans

Cited by 189 publications

References 56 publications

EGFR and HER2 receptor kinase signaling mediate epithelial cell invasion by Candida albicans during oropharyngeal infection

EGFR and HER2 receptor kinase signaling mediate epithelial cell invasion by Candida albicans during oropharyngeal infection

N-Acetylglucosamine (GlcNAc) Induction of Hyphal Morphogenesis and Transcriptional Responses in Candida albicans Are Not Dependent on Its Metabolism

Host Cell Invasion by Medically Important Fungi

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