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Article: Akt phosphorylation of deleted in liver cancer 1 abrogates its suppression of liver cancer tumorigenesis and metastasis

TitleAkt phosphorylation of deleted in liver cancer 1 abrogates its suppression of liver cancer tumorigenesis and metastasis
Authors
KeywordsAkt
Deleted in Liver Cancer 1
Hepatocellular Carcinoma
Phosphorylation
Issue Date2010
PublisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro
Citation
Gastroenterology, 2010, v. 139 n. 4, p. 1397-1407.e6 How to Cite?
AbstractBackground & Aims Deleted in liver cancer 1 (DLC1), which encodes a Rho GTPase activating protein, is a bona fide tumor suppressor in hepatocellular carcinoma. Underexpression of DLC1 in cancer has been attributed to genomic deletion and epigenetic silencing. However, the regulatory mechanism of the tumor suppressive activity of DLC1 remains elusive. In this study, we elucidated a novel post-translational modification by which the activity of DLC1 is functionally regulated. Methods Molecular and biochemical approaches were employed to study Akt phosphorylation of DLC1. In vitro and in vivo functional assays were performed to elucidate the functional significance of Akt phosphorylation of DLC1. Results Phosphorylation of ectopically expressed and endogenous DLC1 was enhanced upon insulin induction or with Akt expression in liver cancer cell lines. Conversely, addition of a phosphatidylinositol 3-kinase/Akt pathway inhibitor or silencing of Akt attenuated the phosphorylation level of DLC1. Site-directed mutagenesis was employed to replace the serine residue of the consensus Akt substrate motifs of DLC1 with alanine. S567 of DLC1 was identified as the only target of Akt phosphorylation. S567 is well conserved in all DLC family members. DLC2 was phosphorylated by Akt at the corresponding residue. Functional assays demonstrated that the S567D phosphomimetic DLC1 mutant lost its inhibitory activities in tumorigenesis and metastasis of oncogenically transformed hepatoblasts in a mouse model. Conclusions This study has revealed a novel post-translational modification that functionally deregulates the biologic activities of DLC1. Phosphorylation of DLC1 and DLC2 by Akt at the conserved residue points to a common regulatory mechanism of the DLC tumor suppressor family. © 2010 AGA Institute.
Persistent Identifierhttp://hdl.handle.net/10722/123835
ISSN
2015 Impact Factor: 18.187
2015 SCImago Journal Rankings: 7.170
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU7798/07M
RGCHKU 1/06C
University of Hong Kong
Funding Information:

Supported by the Hong Kong Research Grants Council (HKU7798/07M), RGC collaborative research grants (HKU 1/06C), and the University of Hong Kong Seed Funding Programme for Basic Research and Outstanding Young Researcher Award (to J.W.P. Yam).

References
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DC FieldValueLanguage
dc.contributor.authorKo, FCFen_HK
dc.contributor.authorChan, LKen_HK
dc.contributor.authorTung, EKKen_HK
dc.contributor.authorLowe, SWen_HK
dc.contributor.authorNg, IOLen_HK
dc.contributor.authorYam, JWPen_HK
dc.date.accessioned2010-10-04T04:27:11Z-
dc.date.available2010-10-04T04:27:11Z-
dc.date.issued2010en_HK
dc.identifier.citationGastroenterology, 2010, v. 139 n. 4, p. 1397-1407.e6en_HK
dc.identifier.issn0016-5085en_HK
dc.identifier.urihttp://hdl.handle.net/10722/123835-
dc.description.abstractBackground & Aims Deleted in liver cancer 1 (DLC1), which encodes a Rho GTPase activating protein, is a bona fide tumor suppressor in hepatocellular carcinoma. Underexpression of DLC1 in cancer has been attributed to genomic deletion and epigenetic silencing. However, the regulatory mechanism of the tumor suppressive activity of DLC1 remains elusive. In this study, we elucidated a novel post-translational modification by which the activity of DLC1 is functionally regulated. Methods Molecular and biochemical approaches were employed to study Akt phosphorylation of DLC1. In vitro and in vivo functional assays were performed to elucidate the functional significance of Akt phosphorylation of DLC1. Results Phosphorylation of ectopically expressed and endogenous DLC1 was enhanced upon insulin induction or with Akt expression in liver cancer cell lines. Conversely, addition of a phosphatidylinositol 3-kinase/Akt pathway inhibitor or silencing of Akt attenuated the phosphorylation level of DLC1. Site-directed mutagenesis was employed to replace the serine residue of the consensus Akt substrate motifs of DLC1 with alanine. S567 of DLC1 was identified as the only target of Akt phosphorylation. S567 is well conserved in all DLC family members. DLC2 was phosphorylated by Akt at the corresponding residue. Functional assays demonstrated that the S567D phosphomimetic DLC1 mutant lost its inhibitory activities in tumorigenesis and metastasis of oncogenically transformed hepatoblasts in a mouse model. Conclusions This study has revealed a novel post-translational modification that functionally deregulates the biologic activities of DLC1. Phosphorylation of DLC1 and DLC2 by Akt at the conserved residue points to a common regulatory mechanism of the DLC tumor suppressor family. © 2010 AGA Institute.en_HK
dc.languageeng-
dc.publisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastroen_HK
dc.relation.ispartofGastroenterologyen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectAkten_HK
dc.subjectDeleted in Liver Cancer 1en_HK
dc.subjectHepatocellular Carcinomaen_HK
dc.subjectPhosphorylationen_HK
dc.titleAkt phosphorylation of deleted in liver cancer 1 abrogates its suppression of liver cancer tumorigenesis and metastasisen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0016-5085&volume=139&issue=4&spage=1397&epage=1407&date=2010&atitle=Akt+phosphorylation+of+deleted+in+liver+cancer+1+abrogates+its+suppression+of+liver+cancer+tumorigenesis+and+metastasis-
dc.identifier.emailNg, IOL:iolng@hkucc.hku.hken_HK
dc.identifier.emailYam, JWP:judyyam@pathology.hku.hken_HK
dc.identifier.authorityNg, IOL=rp00335en_HK
dc.identifier.authorityYam, JWP=rp00468en_HK
dc.description.naturepostprint-
dc.identifier.doi10.1053/j.gastro.2010.06.051en_HK
dc.identifier.pmid20600027-
dc.identifier.scopuseid_2-s2.0-77957372620en_HK
dc.identifier.hkuros172243-
dc.identifier.hkuros183181-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77957372620&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume139en_HK
dc.identifier.issue4en_HK
dc.identifier.spage1397en_HK
dc.identifier.epage1407.e6en_HK
dc.identifier.isiWOS:000282372700049-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study-

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