title: PTEN proteoforms in biology and disease.
abstract: Proteoforms are specific molecular forms of protein products arising from a single gene that possess different structures and different functions. Therefore, a single gene can produce a large repertoire of proteoforms by means of allelic variations (mutations, indels, SNPs), alternative splicing and other pre-translational mechanisms, post-translational modifications (PTMs), conformational dynamics, and functioning. Resulting proteoforms that have different sizes, alternative splicing patterns, sets of post-translational modifications, protein-protein interactions, and protein-ligand interactions, might dramatically increase the functionality of the encoded protein. Herein, we have interrogated the tumor suppressor PTEN for its proteoforms and find that this protein exists in multiple forms with distinct functions and sub-cellular localizations. Furthermore, the levels of each PTEN proteoform in a given cell may affect its biological function. Indeed, the paradigm of the continuum model of tumor suppression by PTEN can be better explained by the presence of a continuum of PTEN proteoforms, diversity, and levels of which are associated with pathological outcomes than simply by the different roles of mutations in the PTEN gene. Consequently, understanding the mechanisms underlying the dysregulation of PTEN proteoforms by several genomic and non-genomic mechanisms in cancer and other diseases is imperative. We have identified different PTEN proteoforms, which control various aspects of cellular function and grouped them into three categories of intrinsic, function-induced, and inducible proteoforms. A special emphasis is given to the inducible PTEN proteoforms that are produced due to alternative translational initiation. The novel finding that PTEN forms dimers with biological implications supports the notion that PTEN proteoform-proteoform interactions may play hitherto unknown roles in cellular homeostasis and in pathogenic settings, including cancer. These PTEN proteoforms with unique properties and functionalities offer potential novel therapeutic opportunities in the treatment of various cancers and other diseases.
authors.affiliation: Department of Pathology and Cell Biology, Morsani College of Medicine, MDC 64, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL, 33612, USA.
authors.forename: Prerna
authors.initials: P
authors.lastname: Malaney
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, Tampa, FL, 33612, USA.|Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave., Saint Petersburg, Russia, 194064.
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
authors.affiliation: Department of Pathology and Cell Biology, Morsani College of Medicine, MDC 64, University of South Florida, 12901 Bruce B Downs Blvd, Tampa, FL, 33612, USA. vdave@health.usf.edu.|Department of Oncological Sciences, Morsani College of Medicine, University of South Florida, Bruce B. Downs Blvd, Tampa, FL, 33612, USA. vdave@health.usf.edu.
authors.forename: Vrushank
authors.initials: V
authors.lastname: Davé
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis; D011487:Protein Conformation; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational
chemical_list: D020033:Protein Isoforms; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Alternative translational initiation; PTEN; Post-translational modifications; Proteoforms