The Experts below are selected from a list of 19680 Experts worldwide ranked by ideXlab platform
Jamie D Weyandt - One of the best experts on this subject based on the ideXlab platform.
-
Activation Of Wild-Type HRAS Suppresses The Earliest Stages Of Pancreatic Cancer
Redox biology, 2015Co-Authors: Jamie D WeyandtAbstract:Background The RAS family of small GTPases is comprised of HRAS , NRAS, and KRAS. KRAS is invariably oncogenically mutated in pancreatic cancers, which is known to induce this disease. Beyond oncogenic KRAS, redox-dependent reactions have been implicated in the activation of the remaining wild-type RAS proteins in pancreatic cancer cell lines. These results suggest a possible involvement of wild-type RAS proteins in pancreatic cancer. Aims To evaluate the impact of genetically suppressing wild-type RAS expression on pancreatic cancer. Methods HRAS homozygous null mice ( HRAS -/- ) were crossed into a Pdx-Cre; LSL-Kras G12D /+ ( KC ) murine background in which oncogenic Kras is activated in the pancreas to promote preinvasive pancreatic cancer. Tumor burden was then measured at different stages of disease. Results HRAS -/- ; KC mice exhibited more precancerous lesions in the pancreas and more off-target skin papillomas compared to their wild-type counterparts, suggesting that HRAS suppresses early oncogenic Kras-driven tumorigenesis, possibly at the time of initiation. Loss of HRAS also reduced the survival of mice engineered to develop aggressive pancreatic cancer by the additional disruption of one allele of the tumor suppressor p53 (Trp53 R172H/+ ). However, this survival advantage was lost when both alleles of Trp53 were mutated, suggesting that wild-type HRAS inhibits tumorigenesis in a p53-dependent fashion. Conclusions Loss of wild-type HRAS promotes the earliest stages of pancreatic tumorigenesis, and moreover results in more rapid progression of the disease. As such, mechanisms leading to activation of wild-type Ras proteins, including but not limited to redox-dependent reactions, may influence the development of pancreatic cancer.
-
Wild-Type HRAS Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer.
PLOS ONE, 2015Co-Authors: Jamie D Weyandt, Benjamin L. Lampson, Sherry Tang, Matthew Mastrodomenico, Diana M. Cardona, Christopher M CounterAbstract:Oncogenic, activating mutations in KRAS initiate pancreatic cancer. There are, however, two other Ras family members, Nras and HRAS, which can be activated in the presence of oncogenic Kras. The role of these wild-type Ras proteins in cancer remains unclear, as their disruption has been shown to enhance or inhibit tumorigenesis depending upon the context. As pancreatic cancer is critically dependent upon Ras signaling, we tested and now report that loss of HRAS increases tumor load and reduces survival in an oncogenic Kras-driven pancreatic adenocarcinoma mouse model. These effects were traced to the earliest stages of pancreatic cancer, suggesting that wild-type HRAS may suppress tumor initiation. In normal cells, activated Ras can suppress proliferation through p53-dependent mechanisms. We find that the tumor suppressive effects of HRAS are nullified in a homozygous mutant p53 background. As such, loss of wild-type HRAS fosters the earliest stages of pancreatic cancer in a p53-dependent manner.
-
abstract 4426 tumor suppressive effects of wild type HRAS on oncogenic kras driven pancreatic tumorigenesis
Cancer Research, 2014Co-Authors: Jamie D Weyandt, Christopher M CounterAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The RAS proteins are a group of small GTPases that can become constitutively activated by point mutations that are found in a quarter or more of all cancer patients, particularly in pancreatic cancer, in which over 90% of patients have an activating KRAS mutation. There are three well-characterized RAS protein family members: HRAS, NRAS, and KRAS, the latter of which is alternatively spliced at the C-terminus into two proteins, KRAS4A and KRAS4B. The RAS proteins are all nearly identical at their N-termini and core effector binding domains. However, they have divergent C-terminal membrane-binding regions that impart both different subcellular localization and subtle changes in signaling. While oncogenic RAS is well established to promote cancer, recent work has suggested that wild-type RAS proteins also participate in tumorigenesis. In this regard, we previously found that wild-type HRAS is activated downstream of oncogenic KRAS, which promoted tumor growth of human pancreatic cancer cell lines. To examine the role of wild-type HRAS during de novo pancreatic tumor development, we tested whether knockout of the wild-type HRAS gene altered tumorigenesis in oncogenic Kras-driven mice models of pancreatic cancer. Specifically, HRAS homozygous null mice (HRAS-/-) were crossed into a Pdx-Cre;LSL-KRasG12D/+ background in the absence or presence of an additional mutant p53 allele (Trp53R172H/+) to induce early and late pancreatic cancer, respectively. Surprisingly, loss of HRAS led to an increase in early pancreatic lesions and reduced survival in the model of late disease. Since HRAS is activated downstream of oncogenic KRAS, and high oncogenic signaling can induce a senescent growth arrest, we tested and found that suppressing senescence by mutating both alleles of Trp53 ameliorated the survival difference between wild-type and null HRAS mice. We thus hypothesize that wild-type HRAS amplifies oncogenic Kras signaling, leading to the growth arrest of senescence and thereby inhibit early tumorigenesis. However, once senescence is suppressed later in tumorigenesis, wild-type RAS proteins instead promote more malignant phenotypes. Citation Format: Jamie D. Weyandt, Christopher M. Counter. Tumor suppressive effects of wild-type HRAS on oncogenic Kras-driven pancreatic tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4426. doi:10.1158/1538-7445.AM2014-4426
Karen W. Gripp - One of the best experts on this subject based on the ideXlab platform.
-
Phenotypic spectrum of Costello syndrome individuals harboring the rare HRAS mutation p.Gly13Asp.
American journal of medical genetics. Part A, 2017Co-Authors: Débora Romeo Bertola, Michelle Buscarilli, Deborah L. Stabley, Laura D. Baker, Daniel Doyle, Dennis Bartholomew, Katia Sol-church, Karen W. GrippAbstract:Costello syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant. These individuals show a homogeneous phenotype. The clinical characteristics of the Costello syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases. Here, we describe the phenotypic spectrum of five additional individuals with HRAS c.38G>A; p.Gly13Asp, including one with somatic mosaicism, and review five previously described cases. The facial and hair abnormalities of the HRAS p.Gly13Asp individuals differ from the typical pattern observed in those showing the common HRAS (p.Gly12Ser) mutation, with less coarse facial features and slow growing, sparse hair with abnormal texture, the latter resembling the pattern observed in Noonan syndrome-like disorder with loose anagen hair and individuals harboring another amino acid substitution in HRAS (p.Gly13Cys). Although some individuals with HRAS p.Gly13Asp developed papillomata and vascular proliferation lesions, no malignant tumors occurred, similar to what was reported for individuals harboring the HRAS p.Gly13Cys. The fact that no malignant tumors were described in these individuals does not allow definitive conclusions about the risk for cancer development. It remains to be determined if substitutions of amino acid 13 in HRAS (p.Gly13Asp and p.Gly13Cys) increase the risk of tumor development.
-
an attenuated phenotype of costello syndrome in three unrelated individuals with a HRAS c 179g a p gly60asp mutation correlates with uncommon functional consequences
American Journal of Medical Genetics Part A, 2015Co-Authors: Karen W. Gripp, Katia Solchurch, Patroula Smpokou, Gail E Graham, David A Stevenson, Heather Hanson, David Viskochil, Laura C Baker, Bridget Russo, Nick GardnerAbstract:Heterozygous germline mutations in the proto-oncogene HRAS cause Costello syndrome (CS), an intellectual disability condition with severe failure to thrive, cardiac abnormalities, predisposition to tumors, and neurologic abnormalities. More than 80% of patients share the HRAS mutation c.34G>A (p.Gly12Ser) associated with the typical, relatively homogeneous phenotype. Rarer mutations occurred in individuals with an attenuated phenotype and less characteristic facial features. Most pathogenic HRAS alterations affect hydrolytic HRAS activity resulting in constitutive activation. "Gain-of-function" and "hyperactivation" concerning downstream pathways are widely used to explain the molecular basis and dysregulation of the RAS-MAPK pathway is the biologic mechanism shared amongst rasopathies. Panel testing for rasopathies identified a novel HRAS mutation (c.179G>A; p.Gly60Asp) in three individuals with attenuated features of Costello syndrome. De novo paternal origin occurred in two, transmission from a heterozygous mother in the third. Individuals showed subtle facial features; curly hair and relative macrocephaly were seen in three; atrial tachycardia and learning difficulties in two, and pulmonic valve dysplasia and mildly thickened left ventricle in one. None had severe failure to thrive, intellectual disability or cancer, underscoring the need to consider HRAS mutations in individuals with an unspecific rasopathy phenotype. Functional studies revealed strongly increased HRAS(Gly60Asp) binding to RAF1, but not to other signaling effectors. Hyperactivation of the MAPK downstream signaling pathways was absent. Our results indicate that an increase in the proportion of activated RAS downstream signaling components does not entirely explain the molecular basis of CS. We conclude that the phenotypic variability in CS recapitulates variable qualities of molecular dysfunction.
-
male to male transmission of costello syndrome g12s HRAS germline mutation inherited from a father with somatic mosaicism
American Journal of Medical Genetics Part A, 2009Co-Authors: Katia Solchurch, Deborah L. Stabley, Laurie A Demmer, Abigail Agbulos, Angela E Lin, Leslie B Smoot, Linda Nicholson, Karen W. GrippAbstract:Costello syndrome is a rare congenital anomaly syndrome associated with mental retardation and predisposition to benign and malignant tumors, caused by heterozygous missense mutations in the HRAS oncogene. Previously, all molecularly analyzed mutations appeared de novo, and most arose in the paternal germline. A single patient with somatic mosaicism for a Costello syndrome causing HRAS mutation has been reported. Here we describe the first documented transmission of an HRAS mutation from a parent with somatic mosaicism to a child with typical Costello syndrome. Prior to the identification of the underlying gene mutation in Costello syndrome, this family had been identified clinically. The proband was subsequently found to carry a G12S HRAS germline mutation. Testing of the parents for parental origin identified his father as mosaic for the same HRAS mutation. The mother was found not to carry an HRAS mutation. The causative familial mutation is identified as a c.34G > A, which is the most common mutation in the HRAS gene in patients with Costello syndrome. The father carries the mutation in 7–8% of his alleles. This is the second case of mosaicism observed in Costello syndrome and the first direct molecular evidence of father-to-son transmission of the disease-causing mutation. Our observation underlines the importance of parental evaluation, and may have implications for genetic counseling and clinical practice. © 2009 Wiley-Liss, Inc.
-
Somatic mosaicism for an HRAS mutation causes Costello syndrome.
American journal of medical genetics. Part A, 2006Co-Authors: Karen W. Gripp, Deborah L. Stabley, Linda Nicholson, Jodi D. Hoffman, Katia Sol-churchAbstract:De novo heterozygous HRAS point mutations have been reported in more than 81 patients with Costello syndrome (CS), but genotype/phenotype correlation remains incomplete because the majority of patients share a common mutation, G12S, seen in 65/81 (80%). Somatic HRAS mutations have previously been identified in solid tumors, and mutation hot spots related to a gain-of-function effect of the gene product are known. The germline mutations causing CS occur at these hot spots and convey a gain-of-function effect, thus accounting for the greatly increased cancer risk. Diagnostic testing for HRAS mutations is now available and the identification of a mutation in a patient with consistent clinical findings confirms a diagnosis of CS. It is not clear yet if the absence of an HRAS mutation precludes a diagnosis of CS. Because there is a significant overlap in the clinical findings of Costello, cardio-facio-cutaneous, and Noonan syndromes, diagnostic uncertainty remains in patients lacking an HRAS mutation. We report here on a female with findings suggestive of CS in whom mutation analysis performed with standard techniques on white blood cell derived DNA did not show an HRAS mutation. However, analysis of DNA derived from three independently collected buccal swabs showed a sequence change qualitatively consistent with the G12S mutation. Allelic quantitation showed the presence of the mutation in approximately 25%-30% of the sampled buccal cells. In this patient, standard technology failed to identify the disease causing mutation on DNA derived from a blood sample, highlighting the potential pitfalls in the interpretation of negative mutation studies. This is the first reported CS patient mosaic for the common HRAS mutation, likely due to a somatic mutation occurring very early in fetal development.
Antonio Gualberto - One of the best experts on this subject based on the ideXlab platform.
-
Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas.
Molecular cancer therapeutics, 2020Co-Authors: Mara Gilardi, Zhiyong Wang, Marco Proietto, Anastasia Chillà, Juan Luis Calleja-valera, Yusuke Goto, Marco Vanoni, Matthew R. Janes, Zbigniew Mikulski, Antonio GualbertoAbstract:Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FTase). FTase catalyzes the posttranslational attachment of farnesyl groups to signaling proteins that are required for localization to cell membranes. Although all RAS isoforms are FTase substrates, only HRAS is exclusively dependent upon farnesylation, raising the possibility that HRAS-mutant tumors might be susceptible to tipifarnib-mediated inhibition of FTase. Here, we report the characterization of tipifarnib activity in a wide panel of HRAS-mutant and wild-type head and neck squamous cell carcinoma (HNSCC) xenograft models. Tipifarnib treatment displaced both mutant and wild-type HRAS from membranes but only inhibited proliferation, survival, and spheroid formation of HRAS-mutant cells. In vivo, tipifarnib treatment induced tumor stasis or regression in all six HRAS-mutant xenografts tested but displayed no activity in six HRAS wild-type patient-derived xenograft (PDX) models. Mechanistically, drug treatment resulted in the reduction of MAPK pathway signaling, inhibition of proliferation, induction of apoptosis, and robust abrogation of neovascularization, apparently via effects on both tumor cells and endothelial cells. Bioinformatics and quantitative image analysis further revealed that FTase inhibition induces progressive squamous cell differentiation in tipifarnib-treated HNSCC PDXs. These preclinical findings support that HRAS represents a druggable oncogene in HNSCC through FTase inhibition by tipifarnib, thereby identifying a precision therapeutic option for HNSCCs harboring HRAS mutations.
-
the aim hn and seq hn study a pivotal study evaluating the efficacy of tipifarnib in patients with head and neck squamous cell carcinoma hnscc with HRAS mutations aim hn and the impact of HRAS mutations on response to first line systemic therapies fo
Journal of Clinical Oncology, 2020Co-Authors: Robert I Haddad, Catherine Rose Scholz, Amanda Psyrri, Kevin J Harrington, Lisa Licitra, Nabil F Saba, Natasa Rajicic, Binaifer Balsara, Michael R Kurman, Antonio GualbertoAbstract:TPS6593Background: HRAS mutations define a unique molecular subset of ~ 5% of HNSCC. Evidence suggests that these tumors respond poorly to standard systemic therapy but the impact of HRAS missense ...
-
a phase ii trial of tipifarnib for patients with previously treated metastatic urothelial carcinoma harboring HRAS mutations
Clinical Cancer Research, 2020Co-Authors: Hye Won Lee, Antonio Gualberto, Catherine Scholz, Hyun Hwan Sung, Byong Chang Jeong, Han Yong Choi, Ghee Young Kwon, Se Hoon ParkAbstract:Purpose: To assess the antitumor activity and safety of tipifarnib, a highly potent and selective farnesyltransferase inhibitor, we performed a phase II clinical trial in patients with advanced and refractory urothelial carcinoma (UC) harboring missense HRAS mutations. Experimental Design: A total of 245 adult patients with previously-treated, advanced UC entered the molecular screening program including HRAS. Those with missense HRAS mutations or STK11:rs2075606 received oral tipifarnib 900 mg bid on days 1-7 and 15-21 of 28-day treatment cycles. The primary endpoint was progression-free survival at 6 months (PFS6). Results: We identified 16 (7%) missense HRAS mutations (G13R, 7; Q61R, 4; G12S, 3; G12C, 2) and 104 (46%) STK11: rs2075606 carriers. In 21 patients enrolled in the study, 14 and 7 patients had missense HRAS mutations and STK11:rs2075606, respectively. The most frequently observed adverse events included fatigue (86%) and hematologic toxicities. With a median follow-up of 28 months, 4 patients (19%) reached PFS6: 3 had missense HRAS mutations and one patient, enrolled as a STK11 carrier, had HRAS frameshift insertions at H27fs and H28fs rendering a nonsense HRAS mutation. The ORR by intent-to-treat analysis was 24% (4 missense and one nonsense frameshift HRAS mutation); no response observed in UC patients with wild type HRAS tumors. Five responses were observed in 12 evaluable patients of 15 with tumors carrying HRAS mutations. Conclusion: Oral tipifarnib resulted in manageable safety profile and encouraging antitumor efficacy against treatment-refractory UC containing HRAS mutations.
-
Abstract 4917: Tipifarnib is highly active in HRAS mutant lung squamous carcinoma tumor models
Experimental and Molecular Therapeutics, 2018Co-Authors: Linda Kessler, Catherine Rose Scholz, Antonio Gualberto, Yi Liu, Francis BurrowsAbstract:Genomic profiling of squamous tumors has revealed important similarities between lung squamous cell carcinoma (LSCC) and head and neck squamous cell carcinoma (HNSCC). For instance, HRAS is the most commonly mutated RAS species in both LSCC and HNSCC, observed in approximately 2% and 5% of cases, respectively (TCGA, Nature 2013). Tipifarnib is a potent and selective inhibitor of farnesyltransferase (FT) that catalyzes the post-translational attachment of farnesyl groups to proteins that require localization to the inner cell membrane. Although all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation, making HRAS mutant tumors uniquely susceptible to tipifarnib mediated inhibition of FT. With limited treatment options, LSCC and HNSCC remain a significant unmet medical need. Recent evidence supports the clinical utility of tipifarnib for treatment of patients with HRAS-mutant HNSCC, and we present herein data supporting a potential utility of tipifarnib in the treatment of HRAS-mutant LSCC. We have characterized the antitumor activity of tipifarnib in CDX and PDX models of squamous cell carcinoma with activating HRAS mutations. Tipifarnib displayed robust antitumor activity in the majority of these models, including lung and head and neck tumors. Six of seven HRAS-mutant lung SCC PDX models responded to tipifarnib treatment with the majority either fully growth-inhibited or undergoing partial or complete regression. Importantly, even LSCC PDX tumors resistant to chemotherapy responded to tipifarnib, suggesting tipifarnib has the potential to offer clinical benefit in patients relapsed or refractory to standard therapies. The activity of tipifarnib in LSCC models is quite similar to that seen in HNSCC PDX models, where tipifarnib also induced regressions consistent with those observed in patients enrolled in the ongoing Phase 2 study in HRAS-mutant SCCHN patients (NCT02383927), including patients refractory to chemotherapy, cetuximab and/or immunotherapy. These data demonstrate that HRAS is a targetable mutation in lung SCC as well as in HNSCC and illustrate the potential for tipifarnib in the treatment of additional HRAS-mutant squamous cell carcinomas. Citation Format: Linda Kessler, Catherine Scholz, Antonio Gualberto, Yi Liu, Francis Burrows. Tipifarnib is highly active in HRAS mutant lung squamous carcinoma tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4917.
Christopher M Counter - One of the best experts on this subject based on the ideXlab platform.
-
Wild-Type HRAS Suppresses the Earliest Stages of Tumorigenesis in a Genetically Engineered Mouse Model of Pancreatic Cancer.
PLOS ONE, 2015Co-Authors: Jamie D Weyandt, Benjamin L. Lampson, Sherry Tang, Matthew Mastrodomenico, Diana M. Cardona, Christopher M CounterAbstract:Oncogenic, activating mutations in KRAS initiate pancreatic cancer. There are, however, two other Ras family members, Nras and HRAS, which can be activated in the presence of oncogenic Kras. The role of these wild-type Ras proteins in cancer remains unclear, as their disruption has been shown to enhance or inhibit tumorigenesis depending upon the context. As pancreatic cancer is critically dependent upon Ras signaling, we tested and now report that loss of HRAS increases tumor load and reduces survival in an oncogenic Kras-driven pancreatic adenocarcinoma mouse model. These effects were traced to the earliest stages of pancreatic cancer, suggesting that wild-type HRAS may suppress tumor initiation. In normal cells, activated Ras can suppress proliferation through p53-dependent mechanisms. We find that the tumor suppressive effects of HRAS are nullified in a homozygous mutant p53 background. As such, loss of wild-type HRAS fosters the earliest stages of pancreatic cancer in a p53-dependent manner.
-
abstract 4426 tumor suppressive effects of wild type HRAS on oncogenic kras driven pancreatic tumorigenesis
Cancer Research, 2014Co-Authors: Jamie D Weyandt, Christopher M CounterAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA The RAS proteins are a group of small GTPases that can become constitutively activated by point mutations that are found in a quarter or more of all cancer patients, particularly in pancreatic cancer, in which over 90% of patients have an activating KRAS mutation. There are three well-characterized RAS protein family members: HRAS, NRAS, and KRAS, the latter of which is alternatively spliced at the C-terminus into two proteins, KRAS4A and KRAS4B. The RAS proteins are all nearly identical at their N-termini and core effector binding domains. However, they have divergent C-terminal membrane-binding regions that impart both different subcellular localization and subtle changes in signaling. While oncogenic RAS is well established to promote cancer, recent work has suggested that wild-type RAS proteins also participate in tumorigenesis. In this regard, we previously found that wild-type HRAS is activated downstream of oncogenic KRAS, which promoted tumor growth of human pancreatic cancer cell lines. To examine the role of wild-type HRAS during de novo pancreatic tumor development, we tested whether knockout of the wild-type HRAS gene altered tumorigenesis in oncogenic Kras-driven mice models of pancreatic cancer. Specifically, HRAS homozygous null mice (HRAS-/-) were crossed into a Pdx-Cre;LSL-KRasG12D/+ background in the absence or presence of an additional mutant p53 allele (Trp53R172H/+) to induce early and late pancreatic cancer, respectively. Surprisingly, loss of HRAS led to an increase in early pancreatic lesions and reduced survival in the model of late disease. Since HRAS is activated downstream of oncogenic KRAS, and high oncogenic signaling can induce a senescent growth arrest, we tested and found that suppressing senescence by mutating both alleles of Trp53 ameliorated the survival difference between wild-type and null HRAS mice. We thus hypothesize that wild-type HRAS amplifies oncogenic Kras signaling, leading to the growth arrest of senescence and thereby inhibit early tumorigenesis. However, once senescence is suppressed later in tumorigenesis, wild-type RAS proteins instead promote more malignant phenotypes. Citation Format: Jamie D. Weyandt, Christopher M. Counter. Tumor suppressive effects of wild-type HRAS on oncogenic Kras-driven pancreatic tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4426. doi:10.1158/1538-7445.AM2014-4426
Laetitia Zona - One of the best experts on this subject based on the ideXlab platform.
-
HRAS signal transduction promotes hepatitis c virus cell entry by triggering assembly of the host tetraspanin receptor complex
Cell Host & Microbe, 2013Co-Authors: Laetitia Zona, Joachim Lupberger, Nazha Sidahmedadrar, C Thumann, Helen J Harris, Amy BarnesAbstract:Hepatitis C virus (HCV) entry is dependent on coreceptor complex formation between the tetraspanin superfamily member CD81 and the tight junction protein claudin-1 (CLDN1) on the host cell membrane. The receptor tyrosine kinase EGFR acts as a cofactor for HCV entry by promoting CD81-CLDN1 complex formation via unknown mechanisms. We identify the GTPase HRAS, activated downstream of EGFR signaling, as a key host signal transducer for EGFR-mediated HCV entry. Proteomic analysis revealed that HRAS associates with tetraspanin CD81, CLDN1, and the previously unrecognized HCV entry cofactors integrin β1 and Ras-related protein Rap2B in hepatocyte membranes. HRAS signaling is required for lateral membrane diffusion of CD81, which enables tetraspanin receptor complex assembly. HRAS was also found to be relevant for entry of other viruses, including influenza. Our data demonstrate that viruses exploit HRAS signaling for cellular entry by compartmentalization of entry factors and receptor trafficking.
-
HRAS signal transduction promotes hepatitis C virus cell entry by triggering assembly of the host tetraspanin receptor complex
Cell Host and Microbe, 2013Co-Authors: Laetitia Zona, Joachim Lupberger, C Thumann, Amy Barnes, N Sidahmed-adrar, H Harris, J Florentin, Rajiv G Tawar, Fei Xiao, Marine TurekAbstract:Hepatitis C virus (HCV) entry is dependent on coreceptor complex formation between the tetraspanin superfamily member CD81 and the tight junction protein claudin-1 (CLDN1) on the host cell membrane. The receptor tyrosine kinase EGFR acts as a cofactor for HCV entry by promoting CD81-CLDN1 complex formation via unknown mechanisms. We identify the GTPase HRAS, activated downstream of EGFR signaling, as a key host signal transducer for EGFR-mediated HCV entry. Proteomic analysis revealed that HRAS associates with tetraspanin CD81, CLDN1, and the previously unrecognized HCV entry cofactors integrin beta1 and Ras-related protein Rap2B in hepatocyte membranes. HRAS signaling is required for lateral membrane diffusion of CD81, which enables tetraspanin receptor complex assembly. HRAS was also found to be relevant for entry of other viruses, including influenza. Our data demonstrate that viruses exploit HRAS signaling for cellular entry by compartmentalization of entry factors and receptor trafficking.