The tumor suppressor activity of DLC1 requires the interaction of its START domain with Phosphatidylserine, PLCD1, and Caveolin-1

Abstract Background DLC1, a tumor suppressor gene that is downregulated in many cancer types by genetic and nongenetic mechanisms, encodes a protein whose RhoGAP and scaffolding activities contribute to its tumor suppressor functions. The role of the DLC1 START (StAR-related lipid transfer; DLC1-STA...

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Autores principales:	Beatriz Sanchez-Solana, Dunrui Wang, Xiaolan Qian, Parthibane Velayoudame, Dhirendra K. Simanshu, Jairaj K. Acharya, Douglas R. Lowy
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	DLC1 Tumor suppressor Rho-GAP Phosphatidylserine PLCD1 Caveolin-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/a367e3987a09471bbf53fecd07797e4f
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spelling	oai:doaj.org-article:a367e3987a09471bbf53fecd07797e4f2021-11-07T12:02:48ZThe tumor suppressor activity of DLC1 requires the interaction of its START domain with Phosphatidylserine, PLCD1, and Caveolin-110.1186/s12943-021-01439-y1476-4598https://doaj.org/article/a367e3987a09471bbf53fecd07797e4f2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12943-021-01439-yhttps://doaj.org/toc/1476-4598Abstract Background DLC1, a tumor suppressor gene that is downregulated in many cancer types by genetic and nongenetic mechanisms, encodes a protein whose RhoGAP and scaffolding activities contribute to its tumor suppressor functions. The role of the DLC1 START (StAR-related lipid transfer; DLC1-START) domain, other than its binding to Caveolin-1, is poorly understood. In other START domains, a key function is that they bind lipids, but the putative lipid ligand for DLC1-START is unknown. Methods Lipid overlay assays and Phosphatidylserine (PS)-pull down assays confirmed the binding of DLC1-START to PS. Co-immunoprecipitation studies demonstrated the interaction between DLC1-START and Phospholipase C delta 1 (PLCD1) or Caveolin-1, and the contribution of PS to those interactions. Rho-GTP, cell proliferation, cell migration, and/or anchorage-independent growth assays were used to investigate the contribution of PS and PLCD1, or the implications of TCGA cancer-associated DLC1-START mutants, to DLC1 functions. Co-immunoprecipitations and PS-pull down assays were used to investigate the molecular mechanisms underlying the impaired functions of DLC1-START mutants. A structural model of DLC1-START was also built to better understand the structural implications of the cancer-associated mutations in DLC1-START. Results We identified PS as the lipid ligand for DLC1-START and determined that DLC1-START also binds PLCD1 protein in addition to Caveolin-1. PS binding contributes to the interaction of DLC1 with Caveolin-1 and with PLCD1. The importance of these activities for tumorigenesis is supported by our analysis of 7 cancer-associated DLC1-START mutants, each of which has reduced tumor suppressor function but retains wildtype RhoGAP activity. Our structural model of DLC1-START indicates the mutants perturb different elements within the structure, which is correlated with our experimental findings that the mutants are heterogenous with regard to the deficiency of their binding properties. Some have reduced PS binding, others reduced PLCD1 and Caveolin-1 binding, and others are deficient for all of these properties. Conclusion These observations highlight the importance of DLC1-START for the tumor suppressor function of DLC1 that is RhoGAP-independent. They also expand the versatility of START domains, as DLC1-START is the first found to bind PS, which promotes the binding to other proteins.Beatriz Sanchez-SolanaDunrui WangXiaolan QianParthibane VelayoudameDhirendra K. SimanshuJairaj K. AcharyaDouglas R. LowyBMCarticleDLC1Tumor suppressorRho-GAPPhosphatidylserinePLCD1Caveolin-1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Cancer, Vol 20, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DLC1 Tumor suppressor Rho-GAP Phosphatidylserine PLCD1 Caveolin-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	DLC1 Tumor suppressor Rho-GAP Phosphatidylserine PLCD1 Caveolin-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Beatriz Sanchez-Solana Dunrui Wang Xiaolan Qian Parthibane Velayoudame Dhirendra K. Simanshu Jairaj K. Acharya Douglas R. Lowy The tumor suppressor activity of DLC1 requires the interaction of its START domain with Phosphatidylserine, PLCD1, and Caveolin-1
description	Abstract Background DLC1, a tumor suppressor gene that is downregulated in many cancer types by genetic and nongenetic mechanisms, encodes a protein whose RhoGAP and scaffolding activities contribute to its tumor suppressor functions. The role of the DLC1 START (StAR-related lipid transfer; DLC1-START) domain, other than its binding to Caveolin-1, is poorly understood. In other START domains, a key function is that they bind lipids, but the putative lipid ligand for DLC1-START is unknown. Methods Lipid overlay assays and Phosphatidylserine (PS)-pull down assays confirmed the binding of DLC1-START to PS. Co-immunoprecipitation studies demonstrated the interaction between DLC1-START and Phospholipase C delta 1 (PLCD1) or Caveolin-1, and the contribution of PS to those interactions. Rho-GTP, cell proliferation, cell migration, and/or anchorage-independent growth assays were used to investigate the contribution of PS and PLCD1, or the implications of TCGA cancer-associated DLC1-START mutants, to DLC1 functions. Co-immunoprecipitations and PS-pull down assays were used to investigate the molecular mechanisms underlying the impaired functions of DLC1-START mutants. A structural model of DLC1-START was also built to better understand the structural implications of the cancer-associated mutations in DLC1-START. Results We identified PS as the lipid ligand for DLC1-START and determined that DLC1-START also binds PLCD1 protein in addition to Caveolin-1. PS binding contributes to the interaction of DLC1 with Caveolin-1 and with PLCD1. The importance of these activities for tumorigenesis is supported by our analysis of 7 cancer-associated DLC1-START mutants, each of which has reduced tumor suppressor function but retains wildtype RhoGAP activity. Our structural model of DLC1-START indicates the mutants perturb different elements within the structure, which is correlated with our experimental findings that the mutants are heterogenous with regard to the deficiency of their binding properties. Some have reduced PS binding, others reduced PLCD1 and Caveolin-1 binding, and others are deficient for all of these properties. Conclusion These observations highlight the importance of DLC1-START for the tumor suppressor function of DLC1 that is RhoGAP-independent. They also expand the versatility of START domains, as DLC1-START is the first found to bind PS, which promotes the binding to other proteins.
format	article
author	Beatriz Sanchez-Solana Dunrui Wang Xiaolan Qian Parthibane Velayoudame Dhirendra K. Simanshu Jairaj K. Acharya Douglas R. Lowy
author_facet	Beatriz Sanchez-Solana Dunrui Wang Xiaolan Qian Parthibane Velayoudame Dhirendra K. Simanshu Jairaj K. Acharya Douglas R. Lowy
author_sort	Beatriz Sanchez-Solana
title	The tumor suppressor activity of DLC1 requires the interaction of its START domain with Phosphatidylserine, PLCD1, and Caveolin-1
title_short	The tumor suppressor activity of DLC1 requires the interaction of its START domain with Phosphatidylserine, PLCD1, and Caveolin-1
title_full	The tumor suppressor activity of DLC1 requires the interaction of its START domain with Phosphatidylserine, PLCD1, and Caveolin-1
title_fullStr	The tumor suppressor activity of DLC1 requires the interaction of its START domain with Phosphatidylserine, PLCD1, and Caveolin-1
title_full_unstemmed	The tumor suppressor activity of DLC1 requires the interaction of its START domain with Phosphatidylserine, PLCD1, and Caveolin-1
title_sort	tumor suppressor activity of dlc1 requires the interaction of its start domain with phosphatidylserine, plcd1, and caveolin-1
publisher	BMC
publishDate	2021
url	https://doaj.org/article/a367e3987a09471bbf53fecd07797e4f
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The tumor suppressor activity of DLC1 requires the interaction of its START domain with Phosphatidylserine, PLCD1, and Caveolin-1

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