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PTEN proteoforms in biology and disease

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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.

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Abbreviations

PTEN:

Phosphatase and tension homolog deleted on chromosome 10

MMAC:

Mutated in multiple advanced cancers

PTP:

Protein tyrosine phosphatases

PI3K:

Phosphatidylinositol-4,5-bisphosphate 3-Kinase

AKT:

V-Akt murine thymoma viral oncogene

PIP3:

Phosphatidylinositol (3,4,5)-trisphosphate

PIP2:

Phosphatidylinositol 4,5-bisphosphate

FAK:

Focal adhesion kinase

CREB:

cAMP responsive element-binding protein

RAB7:

Ras-associated protein RAB7

IRS1:

Insulin receptor substrate 1

PHTS:

PTEN hamartoma tumor syndrome

ASD:

Autism spectrum disorder

SNP:

Single nucleotide polymorphisms

PPI:

Protein–protein interactions

C-tail:

Carboxy terminal tail

PBM:

PIP2-Binding module

C2D:

C2 domain

PDZ:

Post-synaptic density protein (PSD95), Drosophila disc-large tumor suppressor (Dlg1), and Zonula occludens-1 protein (ZO-1)

MoRF:

Molecular recognition features

MAST2:

Microtubule-associated serine/threonine kinase 2

PAR3:

Partitioning defective 3

PTM:

Post-translational modification

NFκB:

Nuclear factor kappa B

DSF:

Differential scanning fluorimetry

CD:

Circular dichroism

FTIR:

Fourier transform infrared spectroscopy

MBH:

Membrane-binding helix

HDX-MS:

Hydrogen/deuterium exchange mass spectrometry

COX:

Cytochrome oxidase c

HDAC:

Histone deacetylase

BCR–ABL:

Breakpoint cluster region–abelson fusion protein

CK2:

Casein Kinase II

CML:

Chronic myelogenous leukemia

TDP:

Top-down proteomics

CRISPR:

Clustered regularly interspaced short palindromic repeats

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Authors and Affiliations

  1. 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

    Prerna Malaney & Vrushank Davé

  2. Department of Molecular Medicine, Morsani College of Medicine, Tampa, FL, 33612, USA

    Vladimir N. Uversky

  3. Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave., Saint Petersburg, Russia, 194064

    Vladimir N. Uversky

  4. Department of Oncological Sciences, Morsani College of Medicine, University of South Florida, Bruce B. Downs Blvd, Tampa, FL, 33612, USA

    Vrushank Davé

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  1. Prerna Malaney
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Malaney, P., Uversky, V.N. & Davé, V. PTEN proteoforms in biology and disease. Cell. Mol. Life Sci. 74, 2783–2794 (2017). https://doi.org/10.1007/s00018-017-2500-6

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