Intrinsically disordered proteins (IDPs) are proteins that lack stable higher order structures fo... more Intrinsically disordered proteins (IDPs) are proteins that lack stable higher order structures for the entire protein molecule or a significant portion of it. The discovery of IDPs evolved as an antithesis to the conventional structure-function paradigm wherein a higher order structure dictates protein function. Over the last decade, a number of proteins with functionally relevant unstructured regions have been discovered, which includes tumor suppressor PTEN. The protein domains that lack structure provide "hot-spots" for post-translational modifications (PTMs) and protein-protein interactions (PPIs), which facilitate their regulation and participation in multiple cellular processes. Consequently, dysregulation in IDPs contribute to aberrant cellular pathophysiology. Herein, we present PTEN and its translational isoform PTEN-L as a hybrid protein possessing ordered domain and intrinsically disordered C-terminal and an N-terminal tails. We review the role of intrinsic disorder in PTEN function and propose a methodology for the use of intrinsic disorder to study PTEN-regulated higher order protein-networks by associating basic principles of network biology to functional pathway analysis at the systems level.
The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidy... more The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] phosphatase activity that directly counteracts the oncogenicity of phosphoinositide 3-kinase (PI3K). PTEN mutations are frequent in tumors and in the germ line of patients with tumor predisposition or with neurological or cognitive disorders, which makes the PTEN gene and protein a major focus of interest in current biomedical research. After almost two decades of intense investigation on the 403-residue-long PTEN protein, a previously uncharacterized form of PTEN has been discovered that contains 173 amino-terminal extra amino acids, as a result of an alternate translation initiation site. To facilitate research in the field and to avoid ambiguities in the naming and identification of PTEN amino acids from publications and databases, we propose here a unifying nomenclature and amino acid numbering for this longer form of PTEN.
The cardiac/slow twitch sarcoplasmic reticulum (SR) Ca 2+-ATPase gene (SERCA2) encodes a calcium ... more The cardiac/slow twitch sarcoplasmic reticulum (SR) Ca 2+-ATPase gene (SERCA2) encodes a calcium transport pump whose expression is regulated in a tissue-and development-specific manner. Previously we have identified two distinct positive ...
Aberrant activation of the PI3K/Akt/mTOR pathway is observed in several cancers and hyper prolife... more Aberrant activation of the PI3K/Akt/mTOR pathway is observed in several cancers and hyper proliferative disorders. PTEN, a tumor suppressor gene, negatively regulates the PI3K/Akt/mTOR pathway. Inhibitors of various components of this pathway are currently being used for cancer therapy. However, the use of these small molecule inhibitors remains limited due to the presence of compensatory feedback loops within the pathway such that inhibition of one oncogenic molecule often results in the activation of another oncogenic molecule resulting in the development of chemoresistance. One novel strategy that has emerged as a means to circumvent the problem of feedback signaling is by activating tumor suppressor genes that abrogate oncogenic pathways and regress tumor growth. In this regard, a newly identified isoform of the PTEN protein shows promise for use in tumors with elevated PI3K/Akt/mTOR signaling. This isoform is a translational variant of PTEN, termed as PTEN Long, and has additional 173 amino acids at its N-terminus (N-173) than normal PTEN. The N-173 region is required for PTEN secretion and transport across the body. Given the potential of this N-173 region to act as a drug delivery system for PTEN, we herein analyze the structural properties of this region. This N-173 tail has a large intrinsically disordered region (IDR) and is composed of highly charged basic residues. Further, the region is enriched in potential linear binding motifs, protein-binding sites and post-translational modifications (PTMs) indicating its probable role in PTEN function and transport across cells. An extensive analysis of this region is warranted to better exploit its structural and biophysical peculiarities to drug discovery and drug delivery applications.
Intrinsically disordered proteins (IDPs) are proteins that lack stable higher order structures fo... more Intrinsically disordered proteins (IDPs) are proteins that lack stable higher order structures for the entire protein molecule or a significant portion of it. The discovery of IDPs evolved as an antithesis to the conventional structure-function paradigm wherein a higher order structure dictates protein function. Over the last decade, a number of proteins with functionally relevant unstructured regions have been discovered, which includes tumor suppressor PTEN. The protein domains that lack structure provide "hot-spots" for post-translational modifications (PTMs) and protein-protein interactions (PPIs), which facilitate their regulation and participation in multiple cellular processes. Consequently, dysregulation in IDPs contribute to aberrant cellular pathophysiology. Herein, we present PTEN and its translational isoform PTEN-L as a hybrid protein possessing ordered domain and intrinsically disordered C-terminal and an N-terminal tails. We review the role of intrinsic disorder in PTEN function and propose a methodology for the use of intrinsic disorder to study PTEN-regulated higher order protein-networks by associating basic principles of network biology to functional pathway analysis at the systems level.
The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidy... more The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] phosphatase activity that directly counteracts the oncogenicity of phosphoinositide 3-kinase (PI3K). PTEN mutations are frequent in tumors and in the germ line of patients with tumor predisposition or with neurological or cognitive disorders, which makes the PTEN gene and protein a major focus of interest in current biomedical research. After almost two decades of intense investigation on the 403-residue-long PTEN protein, a previously uncharacterized form of PTEN has been discovered that contains 173 amino-terminal extra amino acids, as a result of an alternate translation initiation site. To facilitate research in the field and to avoid ambiguities in the naming and identification of PTEN amino acids from publications and databases, we propose here a unifying nomenclature and amino acid numbering for this longer form of PTEN.
The cardiac/slow twitch sarcoplasmic reticulum (SR) Ca 2+-ATPase gene (SERCA2) encodes a calcium ... more The cardiac/slow twitch sarcoplasmic reticulum (SR) Ca 2+-ATPase gene (SERCA2) encodes a calcium transport pump whose expression is regulated in a tissue-and development-specific manner. Previously we have identified two distinct positive ...
Aberrant activation of the PI3K/Akt/mTOR pathway is observed in several cancers and hyper prolife... more Aberrant activation of the PI3K/Akt/mTOR pathway is observed in several cancers and hyper proliferative disorders. PTEN, a tumor suppressor gene, negatively regulates the PI3K/Akt/mTOR pathway. Inhibitors of various components of this pathway are currently being used for cancer therapy. However, the use of these small molecule inhibitors remains limited due to the presence of compensatory feedback loops within the pathway such that inhibition of one oncogenic molecule often results in the activation of another oncogenic molecule resulting in the development of chemoresistance. One novel strategy that has emerged as a means to circumvent the problem of feedback signaling is by activating tumor suppressor genes that abrogate oncogenic pathways and regress tumor growth. In this regard, a newly identified isoform of the PTEN protein shows promise for use in tumors with elevated PI3K/Akt/mTOR signaling. This isoform is a translational variant of PTEN, termed as PTEN Long, and has additional 173 amino acids at its N-terminus (N-173) than normal PTEN. The N-173 region is required for PTEN secretion and transport across the body. Given the potential of this N-173 region to act as a drug delivery system for PTEN, we herein analyze the structural properties of this region. This N-173 tail has a large intrinsically disordered region (IDR) and is composed of highly charged basic residues. Further, the region is enriched in potential linear binding motifs, protein-binding sites and post-translational modifications (PTMs) indicating its probable role in PTEN function and transport across cells. An extensive analysis of this region is warranted to better exploit its structural and biophysical peculiarities to drug discovery and drug delivery applications.
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Papers by Vrushank Davé