Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation

Abstract The p85α protein regulates flux through the PI3K/PTEN signaling pathway, and also controls receptor trafficking via regulation of Rab-family GTPases. In this report, we determined the impact of several cancer patient-derived p85α mutations located within the N-terminal domains of p85α previ...

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Autores principales:	Paul Mellor, Jeremy D. S. Marshall, Xuan Ruan, Dielle E. Whitecross, Rebecca L. Ross, Margaret A. Knowles, Stanley A. Moore, Deborah H. Anderson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/623db4a84b7e4de981307ebca5478389
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spelling	oai:doaj.org-article:623db4a84b7e4de981307ebca54783892021-12-02T16:08:14ZPatient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation10.1038/s41598-018-25487-52045-2322https://doaj.org/article/623db4a84b7e4de981307ebca54783892018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25487-5https://doaj.org/toc/2045-2322Abstract The p85α protein regulates flux through the PI3K/PTEN signaling pathway, and also controls receptor trafficking via regulation of Rab-family GTPases. In this report, we determined the impact of several cancer patient-derived p85α mutations located within the N-terminal domains of p85α previously shown to bind PTEN and Rab5, and regulate their respective functions. One p85α mutation, L30F, significantly reduced the steady state binding to PTEN, yet enhanced the stimulation of PTEN lipid phosphatase activity. Three other p85α mutations (E137K, K288Q, E297K) also altered the regulation of PTEN catalytic activity. In contrast, many p85α mutations reduced the binding to Rab5 (L30F, I69L, I82F, I177N, E217K), and several impacted the GAP activity of p85α towards Rab5 (E137K, I177N, E217K, E297K). We determined the crystal structure of several of these p85α BH domain mutants (E137K, E217K, R262T E297K) for bovine p85α BH and found that the mutations did not alter the overall domain structure. Thus, several p85α mutations found in human cancers may deregulate PTEN and/or Rab5 regulated pathways to contribute to oncogenesis. We also engineered several experimental mutations within the p85α BH domain and identified L191 and V263 as important for both binding and regulation of Rab5 activity.Paul MellorJeremy D. S. MarshallXuan RuanDielle E. WhitecrossRebecca L. RossMargaret A. KnowlesStanley A. MooreDeborah H. AndersonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paul Mellor Jeremy D. S. Marshall Xuan Ruan Dielle E. Whitecross Rebecca L. Ross Margaret A. Knowles Stanley A. Moore Deborah H. Anderson Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation
description	Abstract The p85α protein regulates flux through the PI3K/PTEN signaling pathway, and also controls receptor trafficking via regulation of Rab-family GTPases. In this report, we determined the impact of several cancer patient-derived p85α mutations located within the N-terminal domains of p85α previously shown to bind PTEN and Rab5, and regulate their respective functions. One p85α mutation, L30F, significantly reduced the steady state binding to PTEN, yet enhanced the stimulation of PTEN lipid phosphatase activity. Three other p85α mutations (E137K, K288Q, E297K) also altered the regulation of PTEN catalytic activity. In contrast, many p85α mutations reduced the binding to Rab5 (L30F, I69L, I82F, I177N, E217K), and several impacted the GAP activity of p85α towards Rab5 (E137K, I177N, E217K, E297K). We determined the crystal structure of several of these p85α BH domain mutants (E137K, E217K, R262T E297K) for bovine p85α BH and found that the mutations did not alter the overall domain structure. Thus, several p85α mutations found in human cancers may deregulate PTEN and/or Rab5 regulated pathways to contribute to oncogenesis. We also engineered several experimental mutations within the p85α BH domain and identified L191 and V263 as important for both binding and regulation of Rab5 activity.
format	article
author	Paul Mellor Jeremy D. S. Marshall Xuan Ruan Dielle E. Whitecross Rebecca L. Ross Margaret A. Knowles Stanley A. Moore Deborah H. Anderson
author_facet	Paul Mellor Jeremy D. S. Marshall Xuan Ruan Dielle E. Whitecross Rebecca L. Ross Margaret A. Knowles Stanley A. Moore Deborah H. Anderson
author_sort	Paul Mellor
title	Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation
title_short	Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation
title_full	Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation
title_fullStr	Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation
title_full_unstemmed	Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation
title_sort	patient-derived mutations within the n-terminal domains of p85α impact pten or rab5 binding and regulation
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/623db4a84b7e4de981307ebca5478389
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Patient-derived mutations within the N-terminal domains of p85α impact PTEN or Rab5 binding and regulation

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