{"id":1570,"date":"2023-12-18T02:59:26","date_gmt":"2023-12-18T02:59:26","guid":{"rendered":"https:\/\/medicine.nus.edu.sg\/medphc\/?p=1570"},"modified":"2023-12-18T03:00:41","modified_gmt":"2023-12-18T03:00:41","slug":"shp2-inhibitors-maintain-tgf%ce%b2-signalling-through-smurf2-inhibition","status":"publish","type":"post","link":"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/shp2-inhibitors-maintain-tgf%ce%b2-signalling-through-smurf2-inhibition\/","title":{"rendered":"SHP2 inhibitors maintain TGF\u03b2 signalling through SMURF2 inhibition"},"content":{"rendered":"\r\n<p><strong><span style=\"font-size: 18pt;\">SHP2 inhibitors maintain TGF\u03b2 signalling through SMURF2 inhibition<\/span><\/strong><\/p>\r\n<p>Xianning Lai, Sarah Kit Leng Lui, <strong>Hiu Yan Lam<\/strong>, Yuta Adachi, Wen Jing Sim, Natali Vasilevski, Nicola J. Armstrong, Stephanie Claire Bridgeman,<\/p>\r\n<p>Nathan Michael Main, Tuan Zea Tan, Janina E. E. Tirnitz-Parker, Jean Paul Thiery, Hiromichi Ebi, <strong>Alan Prem Kumar<\/strong>, and Pieter Johan Adam Eichhorn<\/p>\r\n<p><strong>Abstract<\/strong><\/p>\r\n<p>Despite the promising antitumor activity of SHP2 inhibitors in RAS-dependent tumours, overall responses have been limited by<br \/>their narrow therapeutic window. Like with all MAPK pathway inhibitors, this is likely the result of compensatory pathway activation<br \/>mechanisms. However, the underlying mechanisms of resistance to SHP2 inhibition remain unknown. The E3 ligase SMURF2 limits<br \/>TGF\u03b2 activity by ubiquitinating and targeting the TGF\u03b2 receptor for proteosome degradation. Using a functional RNAi screen<br \/>targeting all known phosphatases, we identify that the tyrosine phosphatase SHP2 is a critical regulator of TGF\u03b2 activity. Specifically,<br \/>SHP2 dephosphorylates two key residues on SMURF2, resulting in activation of the enzyme. Conversely, SHP2 depletion maintains<br \/>SMURF2 in an inactive state, resulting in the maintenance of TGF\u03b2 activity. Furthermore, we demonstrate that depleting SHP2 has<br \/>significant implications on TGF\u03b2-mediated migration, senescence, and cell survival. These effects can be overcome through the use<br \/>of TGF\u03b2-targeted therapies. Consequently, our findings provide a rationale for combining SHP2 and TGF\u03b2 inhibitors to enhance<br \/>tumour responses leading to improved patient outcomes.<\/p>\r\n<p><br \/><em>npj Precision Oncology (2023)7:136 ; https:\/\/doi.org\/10.1038\/s41698-023-00486-6<\/em><\/p>\r\n","protected":false},"excerpt":{"rendered":"<p>SHP2 inhibitors maintain TGF\u03b2 signalling through SMURF2 inhibition Xianning Lai, Sarah Kit Leng Lui, Hiu Yan Lam, Yuta Adachi, Wen Jing Sim, Natali Vasilevski, Nicola J. Armstrong, Stephanie Claire Bridgeman, Nathan Michael Main, Tuan Zea Tan, Janina E. E. Tirnitz-Parker, Jean Paul Thiery, Hiromichi Ebi, Alan Prem Kumar, and Pieter Johan Adam Eichhorn Abstract Despite [&hellip;]<\/p>\n","protected":false},"author":9345,"featured_media":1571,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"site-sidebar-layout":"default","site-content-layout":"default","ast-site-content-layout":"default","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"default","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"set","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"categories":[5],"tags":[],"class_list":["post-1570","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-publications"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.4 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>SHP2 inhibitors maintain TGF\u03b2 signalling through SMURF2 inhibition - Pharmacology<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/shp2-inhibitors-maintain-tgf\u03b2-signalling-through-smurf2-inhibition\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"SHP2 inhibitors maintain TGF\u03b2 signalling through SMURF2 inhibition - Pharmacology\" \/>\n<meta property=\"og:description\" content=\"SHP2 inhibitors maintain TGF\u03b2 signalling through SMURF2 inhibition Xianning Lai, Sarah Kit Leng Lui, Hiu Yan Lam, Yuta Adachi, Wen Jing Sim, Natali Vasilevski, Nicola J. Armstrong, Stephanie Claire Bridgeman, Nathan Michael Main, Tuan Zea Tan, Janina E. E. Tirnitz-Parker, Jean Paul Thiery, Hiromichi Ebi, Alan Prem Kumar, and Pieter Johan Adam Eichhorn Abstract Despite [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/shp2-inhibitors-maintain-tgf\u03b2-signalling-through-smurf2-inhibition\/\" \/>\n<meta property=\"og:site_name\" content=\"Pharmacology\" \/>\n<meta property=\"article:published_time\" content=\"2023-12-18T02:59:26+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2023-12-18T03:00:41+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2023\/12\/20231216-APK-pg1-title.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"1700\" \/>\n\t<meta property=\"og:image:height\" content=\"535\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"Woon Fei\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Woon Fei\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"1 minute\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/shp2-inhibitors-maintain-tgf%ce%b2-signalling-through-smurf2-inhibition\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/shp2-inhibitors-maintain-tgf%ce%b2-signalling-through-smurf2-inhibition\/\"},\"author\":{\"name\":\"Woon Fei\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/#\/schema\/person\/ea3ccd10ab2f2bba51fd804396287cb0\"},\"headline\":\"SHP2 inhibitors maintain TGF\u03b2 signalling through SMURF2 inhibition\",\"datePublished\":\"2023-12-18T02:59:26+00:00\",\"dateModified\":\"2023-12-18T03:00:41+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/shp2-inhibitors-maintain-tgf%ce%b2-signalling-through-smurf2-inhibition\/\"},\"wordCount\":232,\"publisher\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/#organization\"},\"image\":{\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/shp2-inhibitors-maintain-tgf%ce%b2-signalling-through-smurf2-inhibition\/#primaryimage\"},\"thumbnailUrl\":\"https:\/\/medicine.nus.edu.sg\/medphc\/wp-content\/uploads\/sites\/33\/2023\/12\/20231216-APK-pg1-title.jpg\",\"articleSection\":[\"Publications\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/shp2-inhibitors-maintain-tgf%ce%b2-signalling-through-smurf2-inhibition\/\",\"url\":\"https:\/\/medicine.nus.edu.sg\/medphc\/publications\/shp2-inhibitors-maintain-tgf%ce%b2-signalling-through-smurf2-inhibition\/\",\"name\":\"SHP2 inhibitors maintain TGF\u03b2 signalling through SMURF2 inhibition - 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