phosphatidylinositol-4-phosphate and Neoplasms

The discovery that apolipoprotein L1 (APOL1) is the trypanolytic factor of human serum raised interest about the function of APOLs, especially following the unexpected finding that in addition to their protective action against sleeping sickness, APOL1 C-terminal variants also cause kidney disease. Based on the analysis of the structure and trypanolytic activity of APOL1, it was proposed that APOLs could function as ion channels of intracellular membranes and be involved in mechanisms triggering programmed cell death. In this review, the recent finding that APOL1 and APOL3 inversely control the synthesis of phosphatidylinositol-4-phosphate (PI(4)P) by the Golgi PI(4)-kinase IIIB (PI4KB) is commented. APOL3 promotes Ca

Topics: Actomyosin; Animals; Apolipoprotein L1; Apolipoproteins L; Autistic Disorder; Autophagosomes; Calcium; Gene Expression Regulation; Golgi Apparatus; Humans; Neoplasms; Phosphatidylinositol Phosphates; Phosphotransferases (Alcohol Group Acceptor); Renal Insufficiency; Schizophrenia; Trypanosomiasis, African; Virus Diseases

Phosphatidylinositol 4-phosphate (PI4P) is a membrane glycerophospholipid and a major regulator of the characteristic appearance of the Golgi complex as well as its vesicular trafficking, signalling and metabolic functions. Phosphatidylinositol 4-kinases, and in particular the PI4KIIIβ isoform, act in concert with PI4P to recruit macromolecular complexes to initiate the biogenesis of trafficking vesicles for several Golgi exit routes. Dysregulation of Golgi PI4P metabolism and the PI4P protein interactome features in many cancers and is often associated with tumour progression and a poor prognosis. Increased expression of PI4P-binding proteins, such as GOLPH3 or PITPNC1, induces a malignant secretory phenotype and the release of proteins that can remodel the extracellular matrix, promote angiogenesis and enhance cell motility. Aberrant Golgi PI4P metabolism can also result in the impaired post-translational modification of proteins required for focal adhesion formation and cell-matrix interactions, thereby potentiating the development of aggressive metastatic and invasive tumours. Altered expression of the Golgi-targeted PI 4-kinases, PI4KIIIβ, PI4KIIα and PI4KIIβ, or the PI4P phosphate Sac1, can also modulate oncogenic signalling through effects on TGN-endosomal trafficking. A Golgi trafficking role for a PIP 5-kinase has been recently described, which indicates that PI4P is not the only functionally important phosphoinositide at this subcellular location. This review charts new developments in our understanding of phosphatidylinositol 4-kinase function at the Golgi and how PI4P-dependent trafficking can be deregulated in malignant disease.

Topics: 1-Phosphatidylinositol 4-Kinase; Animals; Golgi Apparatus; Humans; Membrane Proteins; Membrane Transport Proteins; Neoplasm Proteins; Neoplasms; Phosphatidylinositol Phosphates; Secretory Vesicles

GOLPH3 is a peripheral membrane protein localized to the Golgi and its vesicles, but its purpose had been unclear. We found that GOLPH3 binds specifically to the phosphoinositide phosphatidylinositol(4)phosphate [PtdIns(4)P], which functions at the Golgi to promote vesicle exit for trafficking to the plasma membrane. PtdIns(4)P is enriched at the

Topics: Animals; Biological Transport; Golgi Apparatus; Humans; Membrane Proteins; Neoplasms; Phosphatidylinositol Phosphates

Oxysterol-binding protein (OSBP) and its related proteins (ORPs) constitute a large, evolutionarily conserved family of lipid-binding proteins that are associated with a wide range of cellular activities. The core function of OSBP/ORPs appears to be moving lipids between cellular membranes in a non-vesicular manner. Recent studies have unveiled a novel, counter-transport mechanism of cellular lipid transfer mediated by OSBP/ORPs at the membrane contact sites that involves phosphatidylinositol 4-phosphate. Importantly, the OSBP/ORPs family has also been implicated in cell signalling pathways and cancer development. Here, we summarize recent progress in understanding the role of OSBP/ORPs in cancer development, and discuss how the lipid transfer function of OSBP/ORPs may underpin their role in tumorigenesis.

Topics: Animals; Biological Transport; Cell Membrane; Lipid Metabolism; Neoplasms; Oxysterols; Phosphatidylinositol Phosphates; Receptors, Steroid; Signal Transduction

The type II phosphatidylinositol 4-kinases (PI4KIIs) produce the lipid phosphatidylinositol 4-phosphate (PtdIns4P) and participate in a confusing variety of membrane trafficking and signaling roles. This review argues that both historical and contemporary evidence supports the function of the PI4KIIs in numerous trafficking pathways, and that the key to understanding the enzymatic regulation is through membrane interaction and the intrinsic membrane environment. By summarizing new research and examining the trafficking roles of the PI4KIIs in the context of recently solved molecular structures, I highlight how mechanisms of PI4KII function and regulation are providing insights into the development of cancer and in neurological disease. I present an integrated view connecting the cell biology, molecular regulation, and roles in whole animal systems of these increasingly important proteins.

Topics: 1-Phosphatidylinositol 4-Kinase; Animals; Cell Membrane; Humans; Lipids; Neoplasms; Nervous System Diseases; Phosphatidylinositol Phosphates; Protein Transport; Signal Transduction

The Hedgehog (HH) signaling pathway was discovered originally as a key pathway in embryonic patterning and development. Since its discovery, it has become increasingly clear that the HH pathway also plays important roles in a multitude of cancers. Therefore, HH signaling has emerged as a therapeutic target of interest for cancer therapy. In this review, we provide a brief overview of HH signaling and the key molecular players involved and offer an up-to-date summary of our current knowledge of endogenous and exogenous small molecules that modulate HH signaling. We discuss experiences and lessons learned from the decades-long efforts toward the development of cancer therapies targeting the HH pathway. Challenges to develop next-generation cancer therapies are highlighted.

Topics: Antineoplastic Agents; Cilia; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Neoplasms; Oxysterols; Phosphatidylinositol Phosphates; Signal Transduction; Small Molecule Libraries; Smoothened Receptor

The four mammalian phosphatidylinositol 4-kinases modulate inter-organelle lipid trafficking, phosphoinositide signalling and intracellular vesicle trafficking. In addition to catalytic domains required for the synthesis of PI4P, the phosphatidylinositol 4-kinases also contain isoform-specific structural motifs that mediate interactions with proteins such as AP-3 and the E3 ubiquitin ligase Itch, and such structural differences determine isoform-specific roles in membrane trafficking. Moreover, different permutations of phosphatidylinositol 4-kinase isozymes may be required for a single cellular function such as occurs during distinct stages of GPCR signalling and in Golgi to lysosome trafficking. Phosphatidylinositol 4-kinases have recently been implicated in human disease. Emerging paradigms include increased phosphatidylinositol 4-kinase expression in some cancers, impaired functioning associated with neurological pathologies, the subversion of PI4P trafficking functions in bacterial infection and the activation of lipid kinase activity in viral disease. We discuss how the diverse and sometimes overlapping functions of the phosphatidylinositol 4-kinases present challenges for the design of isoform-specific inhibitors in a therapeutic context.

Topics: 1-Phosphatidylinositol 4-Kinase; Animals; Bacterial Infections; Glycosphingolipids; Humans; Isoenzymes; Neoplasms; Nervous System Diseases; Phosphatidylinositol Phosphates; Receptors, G-Protein-Coupled; Signal Transduction; Sphingomyelins; Virus Diseases

Initially identified as a key phosphoinositide that controls membrane trafficking at the Golgi complex, phosphatidylinositol-4-phosphate (PI4P) has emerged as a key molecule in the regulation of a diverse array of cellular functions. In this review we will discuss selected examples of the findings that in the last few years have significantly increased our awareness of the regulation and roles of PI4P in the Golgi complex and beyond. We will also highlight the role of PI4P in infection and cancer. We believe that, with the increasing number of regulators and effectors of PI4P identified, the time is ripe for a more integrated approach of study. A first step in this direction is the delineation of PI4P-centered molecular networks that we provide using data from low and high throughput studies in yeast and mammals.

Topics: Animals; Cell Line, Tumor; Golgi Apparatus; Humans; Mammals; Neoplasms; Phosphatidylinositol Phosphates; Saccharomyces cerevisiae; Signal Transduction

This article focuses on the emerging roles for phosphatidylinositol 4-phosphate and the phosphatidylinositol 4-kinases in cancer. Phosphatidylinositol 4-phosphate is a common substrate for both the phosphatidylinositol 3-kinase and phospholipase C pathways, and has been implicated in the membrane targeting of proteins such as Girdin/GIV and OSBP. Alterations to phosphatidylinositol 4-kinase expression levels can modulate MAP kinase and Akt signalling, and are important for chemoresistance, tumour angiogenesis and the suppression of apoptosis and metastases. Recent improvements in high-throughput screening assays, and the discoveries that some anti-viral molecules are isoform selective phosphatidylinositol 4-kinase inhibitors have advanced the drugability of these enzymes.

Topics: 1-Phosphatidylinositol 4-Kinase; Antineoplastic Agents; Apoptosis; Drug Resistance, Neoplasm; High-Throughput Screening Assays; Humans; Membrane Lipids; Microfilament Proteins; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Phospholipids; Signal Transduction; Type C Phospholipases; Vesicular Transport Proteins

The type II phosphatidylinositol 4-kinase (PI4KII) enzymes synthesize the lipid phosphatidylinositol 4-phosphate (PI(4)P), which has been detected at the Golgi complex and endosomal compartments and recruits clathrin adaptors. Despite common mechanistic similarities between the isoforms, the extent of their redundancy is unclear. We found that depletion of PI4KIIα and PI4KIIβ using small interfering RNA led to actin remodeling. Depletion of PI4KIIβ also induced the formation of invadopodia containing membrane type I matrix metalloproteinase (MT1-MMP). Depletion of PI4KII isoforms also differentially affected trans-Golgi network (TGN) pools of PI(4)P and post-TGN traffic. PI4KIIβ depletion caused increased MT1-MMP trafficking to invasive structures at the plasma membrane and was accompanied by reduced colocalization of MT1-MMP with membranes containing the endosomal markers Rab5 and Rab7 but increased localization with the exocytic Rab8. Depletion of PI4KIIβ was sufficient to confer an aggressive invasive phenotype on minimally invasive HeLa and MCF-7 cell lines. Mining oncogenomic databases revealed that loss of the PI4K2B allele and underexpression of PI4KIIβ mRNA are associated with human cancers. This finding supports the cell data and suggests that PI4KIIβ may be a clinically significant suppressor of invasion. We propose that PI4KIIβ synthesizes a pool of PI(4)P that maintains MT1-MMP traffic in the degradative pathway and suppresses the formation of invadopodia.

Topics: Cell Line, Tumor; Cell Membrane; Cell Movement; Endosomes; Extracellular Matrix; HeLa Cells; Humans; Isoenzymes; Matrix Metalloproteinase 14; MCF-7 Cells; Minor Histocompatibility Antigens; Neoplasms; Phosphatidylinositol Phosphates; Phosphotransferases (Alcohol Group Acceptor); Podosomes; Protein Transport; RNA, Small Interfering; trans-Golgi Network

Two series of inhibitors of type III phosphatidylinositol-4-kinase were identified by high throughput screening and optimised to derive probe compounds that independently and selectively inhibit the α- and the β-isoforms with no significant activity towards related kinases in the pathway. In a cellular environment, inhibition of the α- but not the β-subtype led to a reduction in phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate concentration, causing inhibition of inositol-1-phosphate formation and inhibition of proliferation in a panel of cancer cell lines.

Topics: 1-Phosphatidylinositol 4-Kinase; Cell Proliferation; High-Throughput Screening Assays; Humans; Inositol Phosphates; Models, Molecular; Molecular Structure; Neoplasms; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositol Phosphates; Protein Kinase Inhibitors; Signal Transduction; Small Molecule Libraries; Tumor Cells, Cultured

Growth factors are proteins or peptides which evoke the replication of the nuclear DNA and thus cell division. A survey is given of the structure, the importance and the mechanism of action of the biochemically exactly characterized growth factors. The epidermal growth factor consists of 53 amino acids and is made over outwardly by proteolysis from a large precursor molecule in the membrane: it is attached to a receptor of the cell membrane consisting of three large parts, by means of which the intracellularly lying part of the receptor becomes effective as proteinkinase and phosphorylizes the parts of the receptor as well as adjacently lying proteins. This acts as a signal for the beginning of the phase of the DNA-synthesis (replication) in the chromosomes. The receptor for the epidermal growth factor has a high degree of structure similarity with the insulin receptor which is also active as proteinkinase after insulin binding. The importance of the decomposition of phosphatidylinosite and of its phosphate esters in binding of certain ligands to receptors is shown.

Topics: Aged; Cell Membrane; Epidermal Growth Factor; ErbB Receptors; Growth Substances; Humans; Interleukin-1; Interleukin-2; Neoplasms; Nerve Growth Factors; Phosphatidylinositol Phosphates; Phosphatidylinositols; Platelet-Derived Growth Factor; Receptors, Cell Surface; Receptors, Nerve Growth Factor; Receptors, Platelet-Derived Growth Factor; Somatomedins