Using Drosophila melanogaster to Dissect the Roles of the mTOR Signaling Pathway in Cell Growth.

The evolutionarily conserved target of rapamycin (TOR) serine/threonine kinase controls eukaryotic cell growth, metabolism and survival by integrating signals from the nutritional status and growth factors. TOR is the catalytic subunit of two distinct functional multiprotein complexes termed mTORC1 (mechanistic target of rapamycin complex 1) and mTORC2, which phosphorylate a different set of substrates and display different physiological functions. Dysregulation of TOR signaling has been involved in the development and progression of several disease states including cancer and diabetes. Here, we highlight how genetic and biochemical studies in the model system Drosophila melanogaster have been crucial to identify the mTORC1 and mTORC2 signaling components and to dissect their function in cellular growth, in strict coordination with insulin signaling. In addition, we review new findings that involve Drosophila Golgi phosphoprotein 3 in regulating organ growth via Rheb-mediated activation of mTORC1 in line with an emerging role for the Golgi as a major hub for mTORC1 signaling.

Cesarean Delivery Trends Among Patients at Low Risk for Cesarean Delivery in the US, 2000-2019.

Importance: Reducing rates of unnecessary cesarean deliveries is both a national and a global health objective. However, there are limited national US data on trends in indications for low-risk cesarean delivery. Objective: To determine temporal trends in and indications for cesarean delivery among patients at low risk for the procedure over a 20-year period. Design, Setting, and Participants: This cross-sectional study analyzed 2000 to 2019 delivery hospitalizations using the National Inpatient Sample. Births at low risk for cesarean delivery were identified using a definition from the Society for Maternal-Fetal Medicine and additional criteria. Temporal trends in cesarean birth were analyzed using joinpoint regression to estimate the average annual percentage change (AAPC) with 95% CIs. Data analysis was performed from August 2022 to January 2023. Exposure: This analysis evaluated cesarean birth trends in a population at low risk for this procedure over a 20-year period. Main Outcomes and Measures: In addition to overall cesarean birth risk, cesarean deliveries for nonreassuring fetal status and labor arrest were individually analyzed. Results: Of an estimated 76.7 million delivery hospitalizations, 21.5 million were excluded according to the Society for Maternal-Fetal Medicine definition, and 14.7 million were excluded according to additional criteria. Of the estimated 40 517 867 deliveries included, 12.1% (4 885 716 deliveries) were by cesarean delivery. Cesarean deliveries among patients at low risk for the procedure increased from 9.7% to 13.9% between 2000 and 2009, plateaued, and then decreased from 13.0% to 11.1% between 2012 and 2019. The AAPC for cesarean delivery was 6.4% (95% CI, 5.2% to 7.6%) from 2000 to 2005, 1.2% from 2005 to 2009 (95% CI, -1.2% to 3.7%), and -2.2% from 2009 to 2019 (95% CI, -2.7% to -1.8%). Cesarean delivery for nonreassuring fetal status increased from 3.4% of all deliveries in 2000 to 5.1% in 2019 (AAPC, 2.1%; 95% CI, 1.7% to 2.5%). Cesarean delivery for labor arrest increased from 3.6% in 2000 to a peak of 4.8% in 2009 before decreasing to 2.7% in 2019. Cesarean deliveries for labor arrest increased during the first half of the study (2000-2009) for the active phase (from 1.5% to 2.1%), latent phase (from 1.1% to 1.5%), and second stage (from 0.9% to 1.3%) and then decreased from 2010 to 2019, from 2.1% to 1.7% for the active phase, from 1.5% to 1.2% for the latent phase, and from 1.2% to 0.9% for the second stage. Conclusions and Relevance: Cesarean deliveries among patients at low risk for cesarean birth appeared to decrease over the latter years of the study period, with cesarean deliveries for labor arrest becoming less common.

Trends in and outcomes associated with obstructive sleep apnea during deliveries in the United States, 2000-2019.

BACKGROUND: Population-level data on obstructive sleep apnea among pregnant women in the United States and associated risk for adverse outcomes during delivery may be of clinical importance and public health significance. OBJECTIVE: This study aimed to assess trends in and outcomes associated with obstructive sleep apnea during delivery hospitalizations. STUDY DESIGN: This repeated cross-sectional study analyzed delivery hospitalizations using the National Inpatient Sample. Temporal trends in obstructive sleep apnea were analyzed using joinpoint regression to estimate the average annual percentage change with 95% confidence intervals. Survey-adjusted logistic regression models were fit to assess the association between obstructive sleep apnea and mechanical ventilation or tracheostomy, acute respiratory distress syndrome, hypertensive disorders of pregnancy, peripartum hysterectomy, pulmonary edema/heart failure, stillbirth, and preterm birth. RESULTS: From 2000 to 2019, an estimated 76,753,013 delivery hospitalizations were identified, of which 54,238 (0.07%) had a diagnosis of obstructive sleep apnea. During the study period, the presence of obstructive sleep apnea during delivery hospitalizations increased from 0.4 to 20.5 cases per 10,000 delivery hospitalizations (average annual percentage change, 20.6%; 95% confidence interval, 19.1-22.2). Clinical factors associated with obstructive sleep apnea included obesity (4.3% of women without and 57.7% with obstructive sleep apnea), asthma (3.2% of women without and 25.3% with obstructive sleep apnea), chronic hypertension (2.0% of women without and 24.5% with obstructive sleep apnea), and pregestational diabetes mellitus (0.9% of women without and 10.9% with obstructive sleep apnea). In adjusted analyses accounting for obesity, other clinical factors, demographics, and hospital characteristics, obstructive sleep apnea was associated with increased odds of mechanical ventilation or tracheostomy (adjusted odds ratio, 21.9; 95% confidence interval, 18.0-26.7), acute respiratory distress syndrome (adjusted odds ratio, 5.9; 95% confidence interval, 5.4-6.5), hypertensive disorders of pregnancy (adjusted odds ratio, 1.6; 95% confidence interval, 1.6-1.7), stillbirth (adjusted odds ratio, 1.2; 95% confidence interval, 1.0-1.4), pulmonary edema/heart failure (adjusted odds ratio, 3.7; 95% confidence interval, 2.9-4.7), peripartum hysterectomy (adjusted odds ratio, 1.66; 95% confidence interval, 1.23-2.23), and preterm birth (adjusted odds ratio, 1.2; 95% confidence interval, 1.1-1.2). CONCLUSION: Obstructive sleep apnea diagnoses are increasingly common in the obstetrical population and are associated with a range of adverse obstetrical outcomes during delivery hospitalizations.

GOLPH3 protein controls organ growth by interacting with TOR signaling proteins in Drosophila.

The oncoprotein GOLPH3 (Golgi phosphoprotein 3) is an evolutionarily conserved phosphatidylinositol 4-phosphate effector, mainly localized to the Golgi apparatus, where it supports organelle architecture and vesicular trafficking. Overexpression of human GOLPH3 correlates with poor prognosis in several cancer types and is associated with enhanced signaling downstream of mTOR (mechanistic target of rapamycin). However, the molecular link between GOLPH3 and mTOR remains elusive. Studies in Drosophila melanogaster have shown that Translationally controlled tumor protein (Tctp) and 14-3-3 proteins are required for organ growth by supporting the function of the small GTPase Ras homolog enriched in the brain (Rheb) during mTORC1 (mTOR complex 1) signaling. Here we demonstrate that Drosophila GOLPH3 (dGOLPH3) physically interacts with Tctp and 14-3-3ζ. RNAi-mediated knockdown of dGOLPH3 reduces wing and eye size and enhances the phenotypes of Tctp RNAi. This phenotype is partially rescued by overexpression of Tctp, 14-3-3ζ, or Rheb. We also show that the Golgi localization of Rheb in Drosophila cells depends on dGOLPH3. Consistent with dGOLPH3 involvement in Rheb-mediated mTORC1 activation, depletion of dGOLPH3 also reduces levels of phosphorylated ribosomal S6 kinase, a downstream target of mTORC1. Finally, the autophagy flux and the expression of autophagic transcription factors of the TFEB family, which anti correlates with mTOR signaling, are compromised upon reduction of dGOLPH3. Overall, our data provide the first in vivo demonstration that GOLPH3 regulates organ growth by directly associating with mTOR signaling proteins.

Microtubule and Actin Cytoskeletal Dynamics in Male Meiotic Cells of Drosophila melanogaster.

Drosophila dividing spermatocytes offer a highly suitable cell system in which to investigate the coordinated reorganization of microtubule and actin cytoskeleton systems during cell division of animal cells. Like male germ cells of mammals, Drosophila spermatogonia and spermatocytes undergo cleavage furrow ingression during cytokinesis, but abscission does not take place. Thus, clusters of primary and secondary spermatocytes undergo meiotic divisions in synchrony, resulting in cysts of 32 secondary spermatocytes and then 64 spermatids connected by specialized structures called ring canals. The meiotic spindles in Drosophila males are substantially larger than the spindles of mammalian somatic cells and exhibit prominent central spindles and contractile rings during cytokinesis. These characteristics make male meiotic cells particularly amenable to immunofluorescence and live imaging analysis of the spindle microtubules and the actomyosin apparatus during meiotic divisions. Moreover, because the spindle assembly checkpoint is not robust in spermatocytes, Drosophila male meiosis allows investigating of whether gene products required for chromosome segregation play additional roles during cytokinesis. Here, we will review how the research studies on Drosophila male meiotic cells have contributed to our knowledge of the conserved molecular pathways that regulate spindle microtubules and cytokinesis with important implications for the comprehension of cancer and other diseases.

Identification of GOLPH3 Partners in Drosophila Unveils Potential Novel Roles in Tumorigenesis and Neural Disorders.

Golgi phosphoprotein 3 (GOLPH3) is a highly conserved peripheral membrane protein localized to the Golgi apparatus and the cytosol. GOLPH3 binding to Golgi membranes depends on phosphatidylinositol 4-phosphate [PI(4)P] and regulates Golgi architecture and vesicle trafficking. GOLPH3 overexpression has been correlated with poor prognosis in several cancers, but the molecular mechanisms that link GOLPH3 to malignant transformation are poorly understood. We recently showed that PI(4)P-GOLPH3 couples membrane trafficking with contractile ring assembly during cytokinesis in dividing Drosophila spermatocytes. Here, we use affinity purification coupled with mass spectrometry (AP-MS) to identify the protein-protein interaction network (interactome) of Drosophila GOLPH3 in testes. Analysis of the GOLPH3 interactome revealed enrichment for proteins involved in vesicle-mediated trafficking, cell proliferation and cytoskeleton dynamics. In particular, we found that dGOLPH3 interacts with the Drosophila orthologs of Fragile X mental retardation protein and Ataxin-2, suggesting a potential role in the pathophysiology of disorders of the nervous system. Our findings suggest novel molecular targets associated with GOLPH3 that might be relevant for therapeutic intervention in cancers and other human diseases.

The Close Relationship between the Golgi Trafficking Machinery and Protein Glycosylation.

Glycosylation is the most common post-translational modification of proteins; it mediates their correct folding and stability, as well as their transport through the secretory transport. Changes in N- and O-linked glycans have been associated with multiple pathological conditions including congenital disorders of glycosylation, inflammatory diseases and cancer. Glycoprotein glycosylation at the Golgi involves the coordinated action of hundreds of glycosyltransferases and glycosidases, which are maintained at the correct location through retrograde vesicle trafficking between Golgi cisternae. In this review, we describe the molecular machinery involved in vesicle trafficking and tethering at the Golgi apparatus and the effects of mutations in the context of glycan biosynthesis and human diseases.

A novel coordinated function of Myosin II with GOLPH3 controls centralspindlin localization during cytokinesis in Drosophila.

In animal cell cytokinesis, interaction of non-muscle myosin II (NMII) with F-actin provides the dominant force for pinching the mother cell into two daughters. Here we demonstrate that celibe (cbe) is a missense allele of zipper, which encodes the Drosophila Myosin heavy chain. Mutation of cbe impairs binding of Zipper protein to the regulatory light chain Spaghetti squash (Sqh). In dividing spermatocytes from cbe males, Sqh fails to concentrate at the equatorial cortex, resulting in thin actomyosin rings that are unable to constrict. We show that cbe mutation impairs localization of the phosphatidylinositol 4-phosphate [PI(4)P]-binding protein Golgi phosphoprotein 3 (GOLPH3, also known as Sauron) and maintenance of centralspindlin at the cell equator of telophase cells. Our results further demonstrate that GOLPH3 protein associates with Sqh and directly binds the centralspindlin subunit Pavarotti. We propose that during cytokinesis, the reciprocal dependence between Myosin and PI(4)P-GOLPH3 regulates centralspindlin stabilization at the invaginating plasma membrane and contractile ring assembly.

Oncogenic Roles of GOLPH3 in the Physiopathology of Cancer.

Golgi phosphoprotein 3 (GOLPH3), a Phosphatidylinositol 4-Phosphate [PI(4)P] effector at the Golgi, is required for Golgi ribbon structure maintenance, vesicle trafficking and Golgi glycosylation. GOLPH3 has been validated as an oncoprotein through combining integrative genomics with clinopathological and functional analyses. It is frequently amplified in several solid tumor types including melanoma, lung cancer, breast cancer, glioma, and colorectal cancer. Overexpression of GOLPH3 correlates with poor prognosis in multiple tumor types including 52% of breast cancers and 41% to 53% of glioblastoma. Roles of GOLPH3 in tumorigenesis may correlate with several cellular activities including: (i) regulating Golgi-to-plasma membrane trafficking and contributing to malignant secretory phenotypes; (ii) controlling the internalization and recycling of key signaling molecules or increasing the glycosylation of cancer relevant glycoproteins; and (iii) influencing the DNA damage response and maintenance of genomic stability. Here we summarize current knowledge on the oncogenic pathways involving GOLPH3 in human cancer, GOLPH3 influence on tumor metabolism and surrounding stroma, and its possible role in tumor metastasis formation.

Drosophila Doublefault protein coordinates multiple events during male meiosis by controlling mRNA translation.

During the extended prophase of Drosophila gametogenesis, spermatocytes undergo robust gene transcription and store many transcripts in the cytoplasm in a repressed state, until translational activation of select mRNAs in later steps of spermatogenesis. Here, we characterize the Drosophila Doublefault (Dbf) protein as a C2H2 zinc-finger protein, primarily expressed in testes, that is required for normal meiotic division and spermiogenesis. Loss of Dbf causes premature centriole disengagement and affects spindle structure, chromosome segregation and cytokinesis. We show that Dbf interacts with the RNA-binding protein Syncrip/hnRNPQ, a key regulator of localized translation in Drosophila We propose that the pleiotropic effects of dbf loss-of-function mutants are associated with the requirement of dbf function for translation of specific transcripts in spermatocytes. In agreement with this hypothesis, Dbf protein binds cyclin B mRNA and is essential for translation of cyclin B in mature spermatocytes.

Familial hypokalemic periodic paralysis in pregnancy: A case report.

Familial hypokalemic periodic paralysis (f-hypoPP) is a rare neuromuscular disorder causing intermittent muscle paralysis. Pregnancy can exacerbate f-hypoPP, yet obstetric management is not well documented. We present a case of a nulliparous woman with f-hypoPP, outlining a complete prenatal care plan generalizable to other women with known f-hypoPP. To our knowledge, this is the first obstetric f-hypoPP case to prioritize intrapartum oral potassium over intravenous potassium, as well as to outline the importance of multidisciplinary care. The patient had a spontaneous vaginal delivery at term with an uneventful postpartum period. Muscle weakness and episodes of relative hypokalemia in the second trimester and during labor were effectively treated with oral potassium supplementation. Care was provided by a multidisciplinary team, and caution was taken to avoid known triggers of paralytic episodes.

Modeling Congenital Disorders of N-Linked Glycoprotein Glycosylation in Drosophila melanogaster.

Protein glycosylation, the enzymatic addition of N-linked or O-linked glycans to proteins, serves crucial functions in animal cells and requires the action of glycosyltransferases, glycosidases and nucleotide-sugar transporters, localized in the endoplasmic reticulum and Golgi apparatus. Congenital Disorders of Glycosylation (CDGs) comprise a family of multisystemic diseases caused by mutations in genes encoding proteins involved in glycosylation pathways. CDGs are classified into two large groups. Type I CDGs affect the synthesis of the dolichol-linked Glc3Man9GlcNac2 precursor of N-linked glycosylation or its transfer to acceptor proteins. Type II CDG (CDG-II) diseases impair either the trimming of the N-linked oligosaccharide, the addition of terminal glycans or the biosynthesis of O-linked oligosaccharides, which occur in the Golgi apparatus. So far, over 100 distinct forms of CDGs are known, with the majority of them characterized by neurological defects including mental retardation, seizures and hypotonia. Yet, it is unclear how defective glycosylation causes the pathology of CDGs. This issue can be only addressed by developing animal models of specific CDGs. Drosophila melanogaster is emerging as a highly suitable organism for analyzing glycan-dependent functions in the central nervous system (CNS) and the involvement of N-glycosylation in neuropathologies. In this review we illustrate recent work that highlights the genetic and neurobiologic advantages offered by D. melanogaster for dissecting glycosylation pathways and modeling CDG pathophysiology.

COG7 deficiency in Drosophila generates multifaceted developmental, behavioral and protein glycosylation phenotypes.

Congenital disorders of glycosylation (CDG) comprise a family of human multisystemic diseases caused by recessive mutations in genes required for protein N-glycosylation. More than 100 distinct forms of CDGs have been identified and most of them cause severe neurological impairment. The Conserved Oligomeric Golgi (COG) complex mediates tethering of vesicles carrying glycosylation enzymes across the Golgi cisternae. Mutations affecting human COG1, COG2 and COG4-COG8 cause monogenic forms of inherited, autosomal recessive CDGs. We have generated a Drosophila COG7-CDG model that closely parallels the pathological characteristics of COG7-CDG patients, including pronounced neuromotor defects associated with altered N-glycome profiles. Consistent with these alterations, larval neuromuscular junctions of Cog7 mutants exhibit a significant reduction in bouton numbers. We demonstrate that the COG complex cooperates with Rab1 and Golgi phosphoprotein 3 to regulate Golgi trafficking and that overexpression of Rab1 can rescue the cytokinesis and locomotor defects associated with loss of Cog7. Our results suggest that the Drosophila COG7-CDG model can be used to test novel potential therapeutic strategies by modulating trafficking pathways.

Rab1 interacts with GOLPH3 and controls Golgi structure and contractile ring constriction during cytokinesis in Drosophila melanogaster.

Cytokinesis requires a tight coordination between actomyosin ring constriction and new membrane addition along the ingressing cleavage furrow. However, the molecular mechanisms underlying vesicle trafficking to the equatorial site and how this process is coupled with the dynamics of the contractile apparatus are poorly defined. Here we provide evidence for the requirement of Rab1 during cleavage furrow ingression in cytokinesis. We demonstrate that the gene omelette (omt) encodes the Drosophila orthologue of human Rab1 and is required for successful cytokinesis in both mitotic and meiotic dividing cells of Drosophila melanogaster We show that Rab1 protein colocalizes with the conserved oligomeric Golgi (COG) complex Cog7 subunit and the phosphatidylinositol 4-phosphate effector GOLPH3 at the Golgi stacks. Analysis by transmission electron microscopy and 3D-SIM super-resolution microscopy reveals loss of normal Golgi architecture in omt mutant spermatocytes indicating a role for Rab1 in Golgi formation. In dividing cells, Rab1 enables stabilization and contraction of actomyosin rings. We further demonstrate that GTP-bound Rab1 directly interacts with GOLPH3 and controls its localization at the Golgi and at the cleavage site. We propose that Rab1, by associating with GOLPH3, controls membrane trafficking and contractile ring constriction during cytokinesis.

Exocyst-Dependent Membrane Addition Is Required for Anaphase Cell Elongation and Cytokinesis in Drosophila.

Mitotic and cytokinetic processes harness cell machinery to drive chromosomal segregation and the physical separation of dividing cells. Here, we investigate the functional requirements for exocyst complex function during cell division in vivo, and demonstrate a common mechanism that directs anaphase cell elongation and cleavage furrow progression during cell division. We show that onion rings (onr) and funnel cakes (fun) encode the Drosophila homologs of the Exo84 and Sec8 exocyst subunits, respectively. In onr and fun mutant cells, contractile ring proteins are recruited to the equatorial region of dividing spermatocytes. However, cytokinesis is disrupted early in furrow ingression, leading to cytokinesis failure. We use high temporal and spatial resolution confocal imaging with automated computational analysis to quantitatively compare wild-type versus onr and fun mutant cells. These results demonstrate that anaphase cell elongation is grossly disrupted in cells that are compromised in exocyst complex function. Additionally, we observe that the increase in cell surface area in wild type peaks a few minutes into cytokinesis, and that onr and fun mutant cells have a greatly reduced rate of surface area growth specifically during cell division. Analysis by transmission electron microscopy reveals a massive build-up of cytoplasmic astral membrane and loss of normal Golgi architecture in onr and fun spermatocytes, suggesting that exocyst complex is required for proper vesicular trafficking through these compartments. Moreover, recruitment of the small GTPase Rab11 and the PITP Giotto to the cleavage site depends on wild-type function of the exocyst subunits Exo84 and Sec8. Finally, we show that the exocyst subunit Sec5 coimmunoprecipitates with Rab11. Our results are consistent with the exocyst complex mediating an essential, coordinated increase in cell surface area that potentiates anaphase cell elongation and cleavage furrow ingression.

The multiple cellular functions of the oncoprotein Golgi phosphoprotein 3.

The highly conserved Golgi phosphoprotein 3 (GOLPH3) protein, a component of Trans-Golgi Network (TGN), has been defined as a "first-in-class Golgi oncoprotein" and characterized as a Phosphatidylinositol 4-phosphate [PI(4)P] effector at the Golgi. GOLPH3 is commonly amplified in several solid tumors. Furthermore this protein has been associated with poor prognosis in many cancers. Highly conserved from yeast to humans, GOLPH3 provides an essential function in vesicle trafficking and Golgi structure. Recent data have also implicated this oncoprotein in regulation of cytokinesis, modulation of mitochondrial mass and cellular response to DNA damage. A minute dissection of the molecular pathways that require GOLPH3 protein will be helpful to develop new therapeutic cancer strategies.

The roles of the oncoprotein GOLPH3 in contractile ring assembly and membrane trafficking during cytokinesis.

Cytokinesis is an intricate process that requires an intimate interplay between actomyosin ring constriction and plasma membrane remodelling at the cleavage furrow. However, the molecular mechanisms involved in coupling the cytoskeleton dynamics with vesicle trafficking during cytokinesis are poorly understood. The highly conserved Golgi phosphoprotein 3 (GOLPH3), functions as a phosphatidylinositol 4-phosphate (PI4P) effector at the Golgi. Recent studies have suggested that GOLPH3 is up-regulated in several cancers and is associated with poor prognosis and more aggressive tumours. In Drosophila melanogaster, GOLPH3 localizes at the cleavage furrow of dividing cells, is required for successful cytokinesis and acts as a key molecule in coupling phosphoinositide (PI) signalling with actomyosin ring dynamics. Because cytokinesis failures have been linked with pre-malignant disease and cancer, the novel connection between GOLPH3 and cytokinesis imposes new fields of investigation in cancer biology and therapy.

GOLPH3 is essential for contractile ring formation and Rab11 localization to the cleavage site during cytokinesis in Drosophila melanogaster.

The highly conserved Golgi phosphoprotein 3 (GOLPH3) protein has been described as a Phosphatidylinositol 4-phosphate [PI(4)P] effector at the Golgi. GOLPH3 is also known as a potent oncogene, commonly amplified in several human tumors. However, the molecular pathways through which the oncoprotein GOLPH3 acts in malignant transformation are largely unknown. GOLPH3 has never been involved in cytokinesis. Here, we characterize the Drosophila melanogaster homologue of human GOLPH3 during cell division. We show that GOLPH3 accumulates at the cleavage furrow and is required for successful cytokinesis in Drosophila spermatocytes and larval neuroblasts. In premeiotic spermatocytes GOLPH3 protein is required for maintaining the organization of Golgi stacks. In dividing spermatocytes GOLPH3 is essential for both contractile ring and central spindle formation during cytokinesis. Wild type function of GOLPH3 enables maintenance of centralspindlin and Rho1 at cell equator and stabilization of Myosin II and Septin rings. We demonstrate that the molecular mechanism underlying GOLPH3 function in cytokinesis is strictly dependent on the ability of this protein to interact with PI(4)P. Mutations that abolish PI(4)P binding impair recruitment of GOLPH3 to both the Golgi and the cleavage furrow. Moreover telophase cells from mutants with defective GOLPH3-PI(4)P interaction fail to accumulate PI(4)P-and Rab11-associated secretory organelles at the cleavage site. Finally, we show that GOLPH3 protein interacts with components of both cytokinesis and membrane trafficking machineries in Drosophila cells. Based on these results we propose that GOLPH3 acts as a key molecule to coordinate phosphoinositide signaling with actomyosin dynamics and vesicle trafficking during cytokinesis. Because cytokinesis failures have been associated with premalignant disease and cancer, our studies suggest novel insight into molecular circuits involving the oncogene GOLPH3 in cytokinesis.