title: Controlling PTEN (Phosphatase and Tensin Homolog) Stability: A DOMINANT ROLE FOR LYSINE 66.
abstract: Phosphatase and tensin homolog (PTEN) is a phosphoinositide lipid phosphatase and one of the most frequently disrupted tumor suppressors in many forms of cancer, with even small reductions in the expression levels of PTEN promoting cancer development. Although the post-translational ubiquitination of PTEN can control its stability, activity, and localization, a detailed understanding of how PTEN ubiquitination integrates with other cellular regulatory processes and may be dysregulated in cancer has been hampered by a poor understanding of the significance of ubiquitination at individual sites. Here we show that Lys(66) is not required for cellular activity, yet dominates over other PTEN ubiquitination sites in the regulation of protein stability. Notably, combined mutation of other sites (Lys(13), Lys(80), and Lys(289)) has relatively little effect on protein expression, protein stability, or PTEN polyubiquitination. The present work identifies a key role for Lys(66) in the regulation of PTEN expression and provides both an opportunity to improve the stability of PTEN as a protein therapy and a mechanistic basis for efforts to stabilize endogenous PTEN.
authors.affiliation: From the Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot Watt University, James Nasmyth Building, Riccarton Campus, Edinburgh EH14 4AS, United Kingdom amit.gupta@icr.ac.uk.
authors.forename: Amit
authors.initials: A
authors.lastname: Gupta
authors.affiliation: From the Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot Watt University, James Nasmyth Building, Riccarton Campus, Edinburgh EH14 4AS, United Kingdom n.r.leslie@hw.ac.uk.
authors.forename: Nicholas R
authors.identifier: 0000-0001-5131-0541
authors.initials: NR
authors.lastname: Leslie
mesh_terms: D045744:Cell Line, Tumor; D004795:Enzyme Stability / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D008239:Lysine
keywords: cancer; phosphatase; phosphatase and tensin homolog (PTEN); phosphoinositide; phosphoinositide 3-kinase; protein stability; tumor suppressor; ubiquitylation (ubiquitination)