The nuclear envelope (NE) forms a barrier between the nucleus and the cytosol that preserves genomic integrity. The nuclear lamina and nuclear pore complexes (NPC) are NE components that regulate nuclear events through interaction with other proteins and DNA. Defects in nuclear lamina are associated with the development of laminopathies. As cells depleted of phosphoinositide-3-kinase beta (PI3K?) showed aberrant nuclear morphology, we studied the contribution of PI3K? to maintenance of NE integrity. pik3cb depletion reduced the nuclear membrane tension, triggered formation of areas of lipid bilayer/lamina discontinuity, and impaired NPC assembly. We show that one mechanism for PI3K? regulation of NE/NPC integrity is its association to RCC1 (regulator of chromosome condensation 1), the activator of nuclear Ran GTPase. PI3K? controls RCC1 binding to chromatin and in turn, Ran activation. These findings suggest that PI3K? regulates the nuclear envelope through upstream regulation of RCC1 and Ran.
IgG aPL against domain I of ?2-glycoprotein I (?2GPI) [anti-DI (aDI)] is associated with the pathogenesis of APS, an autoimmune disease defined by thrombosis and pregnancy morbidity. To date, however, no study has demonstrated direct pathogenicity of IgG aDI in vivo. In this proof-of-concept study, we designed a novel system to affinity purify polyclonal aDI aPL in order to assess its prothrombotic ability in a well-characterized mouse microcirculation model for APS.
The acquisition of invasiveness is characteristic of tumor progression. Numerous genetic changes are associated with metastasis, but the mechanism by which a cell becomes invasive remains unclear. Expression of p85?, a regulatory subunit of phosphoinositide-3-kinase, markedly increases in advanced carcinoma, but its mode of action is unknown. We postulated that p85? might facilitate cell invasion. We show that p85? localized at cell adhesions in complex with focal adhesion kinase and enhanced stability and maturation of cell adhesions. In addition, p85? induced development at cell adhesions of an F-actin core that extended several microns into the cell z-axis resembling the skeleton of invadopodia. p85? lead to F-actin polymerization at cell adhesions by recruiting active Cdc42/Rac at these structures. In accordance with p85? function in invadopodium-like formation, p85? levels increased in metastatic melanoma and p85? depletion reduced invadopodium formation and invasion. These results show that p85? enhances invasion by inducing cell adhesion development into invadopodia-like structures explaining the metastatic potential of tumors with increased p85? levels.
The phosphoinositide 3-kinase (PI3K)/PTEN (phosphatase and tensin homolog) pathway is one of the central routes that enhances cell survival, division, and migration, and it is frequently deregulated in cancer. PI3K catalyzes formation of phosphatidylinositol 3,4,5-triphosphate [PI(3,4,5)P3] after cell activation; PTEN subsequently reduces these lipids to basal levels. Activation of the ubiquitous p110? isoform precedes that of p110? at several points during the cell cycle. We studied the potential connections between p110? and p110? activation, and we show that cell stimulation promotes p110? and p110? association, demonstrating oligomerization of PI3K catalytic subunits within cells. Cell stimulation also promoted PTEN incorporation into this complex, which was necessary for PTEN activation. Our results show that PI3Ks dimerize in vivo and that PI3K and PTEN activities modulate each other in a complex that controls cell PI(3,4,5)P3 levels.
Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease generated and maintained throughout life by autoreactive T and B cells. Class I phosphoinositide 3-kinases (PI3K) are heterodimers composed of a regulatory and a catalytic subunit that catalyze phosphoinositide-3,4,5-P3 formation and regulate cell survival, migration, and division. Activity of the PI3K? isoform is enhanced in human SLE patient PBLs. In this study, we analyzed the effect of inhibiting PI3K? in MRL/lpr mice, a model of human SLE. We found that PI3K? inhibition ameliorated lupus progression. Treatment of these mice with a PI3K? inhibitor reduced the excessive numbers of CD4(+) effector/memory cells and B cells. In addition, this treatment reduced serum TNF-? levels and the number of macrophages infiltrating the kidney. Expression of inactive PI3K?, but not deletion of the other hematopoietic isoform PI3K?, reduced the ability of macrophages to cross the basement membrane, a process required to infiltrate the kidney, explaining MRL/lpr mice improvement by pharmacologic inhibition of PI3K?. The observations that p110? inhibitor prolonged mouse life span, reduced disease symptoms, and showed no obvious secondary effects indicates that PI3K? is a promising target for SLE.
To determine if proinflammatory and prothrombotic biomarkers are differentially upregulated in persistently antiphospholipid antibody (aPL)-positive patients, and to examine the effects of fluvastatin on these biomarkers.
Sublingual administration of Phleum pratense allergen immunotherapy (SLIT) tablets is a clinically efficient treatment for grass pollen-induced rhinoconjunctivitis. This immunotherapy downregulates TH2 immune responses, induces tolerogenic pathways, and increases regulatory T cells. However, associated immune response markers of allergen desensitization remain undefined.
The migratory route of neural progenitor/precursor cells (NPC) has a central role in central nervous system development. Although the role of the chemokine CXCL12 in NPC migration has been described, the intracellular signaling cascade involved remains largely unclear. Here we studied the molecular mechanisms that promote murine NPC migration in response to CXCL12, in vitro and ex vivo. Migration was highly dependent on signaling by the CXCL12 receptor, CXCR4. Although the JAK/STAT pathway was activated following CXCL12 stimulation of NPC, JAK activity was not necessary for NPC migration in vitro. Whereas CXCL12 activated the PI3K catalytic subunits p110? and p110? in NPC, only p110? participated in CXCL12-mediated NPC migration. Ex vivo experiments using organotypic slice cultures showed that p110? blockade impaired NPC exit from the medial ganglionic eminence. In vivo experiments using in utero electroporation nonetheless showed that p110? is dispensable for radial migration of pyramidal neurons. We conclude that PI3K p110? is activated in NPC in response to CXCL12, and its activity is necessary for immature interneuron migration to the cerebral cortex.
The role of p110? PI3K in lymphoid cells has been studied extensively, showing its importance in immune cell differentiation, activation and development. Altered T cell localization in p110?-deficient mouse spleen suggested a role for p110? in non-hematopoietic stromal cells, which maintain hematopoietic cell segregation. We tested this hypothesis using p110?(WT/WT) mouse bone marrow to reconstitute lethally irradiated p110?(WT/WT) or p110?(D910A/D910A) (which express catalytically inactive p110?) recipients, and studied localization, number and percentage of hematopoietic cell subsets in spleen and lymph nodes, in homeostatic conditions and after antigen stimulation. These analyses showed diffuse T cell areas in p110?(D910A/D910A) and in reconstituted p110?(D910A/D910A) mice in homeostatic conditions. In these mice, spleen CD4(+) and CD8(+) T cell numbers did not increase in response to antigen, suggesting that a p110?(D910A/D910A) stroma defect impedes correct T cell response. FACS analysis of spleen stromal cell populations showed a decrease in the percentage of gp38(-)CD31(+) cells in p110?(D910A/D910A) mice. qRT-PCR studies detected p110? mRNA expression in p110?(WT/WT) spleen gp38(-)CD31(+) and gp38(+)CD31(+) subsets, which was reduced in p110?(D910A/D910A) spleen. Lack of p110? activity in these cell populations correlated with lower LT?R, CCL19 and CCL21 mRNA levels; these molecules participate in T cell localization to specific spleen areas. Our results could explain the lower T cell numbers and more diffuse T cell areas found in p110?(D910A/D910A) mouse spleen, as well as the lower T cell expansion after antigen stimulation in p110?(D910A/D910A) compared with p110?(WT/WT) mice.
Atherosclerosis is an inflammatory disease regulated by infiltrating monocytes and T cells, among other cell types. Macrophage recruitment to atherosclerotic lesions is controlled by monocyte infiltration into plaques. Once in the lesion, macrophage proliferation in situ, apoptosis, and differentiation to an inflammatory (M1) or anti-inflammatory phenotype (M2) are involved in progression to advanced atherosclerotic lesions. We studied the role of phosphoinositol-3-kinase (PI3K) p110? in the regulation of in situ apoptosis, macrophage proliferation and polarization towards M1 or M2 phenotypes in atherosclerotic lesions. We analyzed atherosclerosis development in LDLR(-/-)p110?(+/-) and LDLR(-/-)p110?(-/-) mice, and performed expression and functional assays in tissues and primary cells from these and from p110?(+/-) and p110?(-/-) mice. Lack of p110? in LDLR(-/-) mice reduces the atherosclerosis burden. Atherosclerotic lesions in fat-fed LDLR(-/-)p110?(-/-) mice were smaller than in LDLR(-/-)p110?(+/-) controls, which coincided with decreased macrophage proliferation in LDLR(-/-)p110?(-/-) mouse lesions. This proliferation defect was also observed in p110?(-/-) bone marrow-derived macrophages (BMM) stimulated with macrophage colony-stimulating factor (M-CSF), and was associated with higher intracellular cyclic adenosine monophosphate (cAMP) levels. In contrast, T cell proliferation was unaffected in LDLR(-/-)p110?(-/-) mice. Moreover, p110? deficiency did not affect macrophage polarization towards the M1 or M2 phenotypes or apoptosis in atherosclerotic plaques, or polarization in cultured BMM. Our results suggest that higher cAMP levels and the ensuing inhibition of macrophage proliferation contribute to atheroprotection in LDLR(-/-) mice lacking p110?. Nonetheless, p110? deletion does not appear to be involved in apoptosis, in macrophage polarization or in T cell proliferation.
Global mechanisms defining the gene expression programs specific for hematopoiesis are still not fully understood. Here, we show that promoter DNA demethylation is associated with the activation of hematopoietic-specific genes. Using genome-wide promoter methylation arrays, we identified 694 hematopoietic-specific genes repressed by promoter DNA methylation in human embryonic stem cells and whose loss of methylation in hematopoietic can be associated with gene expression. The association between promoter methylation and gene expression was studied for many hematopoietic-specific genes including CD45, CD34, CD28, CD19, the T cell receptor (TCR), the MHC class II gene HLA-DR, perforin 1 and the phosphoinositide 3-kinase (PI3K) and results indicated that DNA demethylation was not always sufficient for gene activation. Promoter demethylation occurred either early during embryonic development or later on during hematopoietic differentiation. Analysis of the genome-wide promoter methylation status of induced pluripotent stem cells (iPSCs) generated from somatic CD34(+) HSPCs and differentiated derivatives from CD34(+) HSPCs confirmed the role of DNA methylation in regulating the expression of genes of the hemato-immune system, and indicated that promoter methylation of these genes may be associated to stemness. Together, these data suggest that promoter DNA demethylation might play a role in the tissue/cell-specific genome-wide gene regulation within the hematopoietic compartment.
Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease caused by the action of autoreactive T and B cells. Class I phosphoinositide-3-kinases (PI3K) are enzymes that trigger formation of 3-poly-phosphoinositides that induce cell survival. Enhanced PI3K activation is a frequent event in human cancer. Nonetheless, in a genetic model with enhanced activation of class I(A) PI3K in T cells, mice show a greater tumor index but die of a lupus-like disease. In this study, we studied the potential PI3K involvement in human SLE. The PI3K pathway was frequently activated in SLE patient PBMC and T cells (?70% of cases), more markedly in active disease phases. We examined the mechanism for PI3K pathway activation and found enhanced activation of PI3K? in SLE peripheral blood T cells. The magnitude of PI3K pathway activation in patients paralleled activated/memory T cell accumulation. We examined potential tolerance mechanisms affected by increased PI3K activity; SLE patients showed reduced activation-induced cell death of activated/memory T cells. Moreover, the defective activation-induced cell death in SLE T cells was corrected after reduction of PI3K? activity, suggesting that PI3K? contributes to induction of enhanced SLE memory T cell survival. These observations point to PI3K? as a target of clinical interest for SLE.
The objective was to offer to the clinical researchers who work on elderly and health field a review of the main instruments use for assessment the presence of comorbidity in elderly. A systematic quest at Medline using keywords was made. A group of experts on geriatric and internal medicine physicians was integrated for the evaluation of paper found. The group analyzed the structure, clinical utility, clinimetrics properties, focus on elderly patients. This communication included the four main tools: Charlsons comorbidity index, Geriatric index of comorbidity, Kaplan-Feinsteins index and Cumulative Illness Rating Scale-Geriatric (CIRS-G). Each of them showed adequate clinometric properties, although, the assessment of CIRS-G requires a health professional more skilled on clinical examination, all of these indexes have been shown to have a good predictive value about functional impairment and mortality. However, the choice of the index by researchers depends on the context of the study.
Class I(A) phosphoinositide 3-kinases (PI3Ks) are heterodimeric enzymes composed of a p85 regulatory and a p110 catalytic subunit that induce the formation of 3-polyphosphoinositides, which mediate cell survival, division, and migration. There are two ubiquitous PI3K isoforms p110? and p110? that have nonredundant functions in embryonic development and cell division. However, whereas p110? concentrates in the cytoplasm, p110? localizes to the nucleus and modulates nuclear processes such as DNA replication and repair. At present, the structural features that determine p110? nuclear localization remain unknown. We describe here that association with the p85? regulatory subunit controls p110? nuclear localization. We identified a nuclear localization signal (NLS) in p110? C2 domain that mediates its nuclear entry, as well as a nuclear export sequence (NES) in p85?. Deletion of p110? induced apoptosis, and complementation with the cytoplasmic C2-NLS p110? mutant was unable to restore cell survival. These studies show that p110? NLS and p85? NES regulate p85?/p110? nuclear localization, supporting the idea that nuclear, but not cytoplasmic, p110? controls cell survival.
Class I phosphoinositide 3-kinases are enzymes that generate 3-poly-phosphoinositides at the cell membrane following transmembrane receptor stimulation. Expression of the phosphoinositide 3-kinase beta (PI3Kbeta) isoform, but not its activity, is essential for early embryonic development. Nonetheless, the specific function of PI3Kbeta in the cell remains elusive. Double-strand breaks (DSB) are among the most deleterious lesions for genomic integrity; their repair is required for development. We show that PI3Kbeta is necessary for DSB sensing, as PI3Kbeta regulates binding of the Nbs1 sensor protein to damaged DNA. Indeed, Nbs1 did not bind to DSB in PI3Kbeta-deficient cells, which showed a general defect in subsequent ATM and ATR activation, resulting in genomic instability. Inhibition of PI3Kbeta also retarded the DNA repair but the defect was less marked than that induced by PI3Kbeta deletion, supporting a kinase-independent function for PI3Kbeta in DNA repair. These results point at class I PI3Kbeta as a critical sensor of genomic integrity.
Macropinocytosis is regulated by Abl kinase via an unknown mechanism. We previously demonstrated that Abl kinase activity is, itself, regulated by Abi1 subsequent to Abl kinase phosphorylation of Abi1 tyrosine 213 (pY213) . Here we show that blocking phosphorylation of Y213 abrogated the ability of Abl to regulate macropinocytosis, implicating Abi1 pY213 as a key regulator of macropinocytosis. Results from screening the human SH2 domain library and mapping the interaction site between Abi1 and the p85 regulatory domain of PI-3 kinase, coupled with data from cells transfected with loss-of-function p85 mutants, support the hypothesis that macropinocytosis is regulated by interactions between Abi1 pY213 and the C-terminal SH2 domain of p85-thereby linking Abl kinase signaling to p85-dependent regulation of macropinocytosis.
Tumor dissemination is a complex process, in which certain steps resemble those in leukocyte homing. Specific chemokine/chemokine receptor pairs have important roles in both processes. CXCL12/CXCR4 is the most commonly expressed chemokine/chemokine receptor pair in human cancers, in which it regulates cell adhesion, extravasation, metastatic colonization, angiogenesis, and proliferation. All of these processes require activation of signaling pathways that include G proteins, phosphatidylinositol-3 kinase (PI3K), JAK kinases, Rho GTPases, and focal adhesion-associated proteins. We analyzed these pathways in a human melanoma cell line in response to CXCL12 stimulation, and found that PI3Kgamma regulates tumor cell adhesion through mechanisms different from those involved in cell invasion. Our data indicate that, following CXCR4 activation after CXCL12 binding, the invasion and adhesion processes are regulated differently by distinct downstream events in these signaling cascades.
Recent clinical reports suggest that intraneural needle placement may not always lead to neurologic injury. To explain the absence of neurologic complications in these reports, we studied the risk and extent of nerve injury after intentional needle-nerve placement in a cryopreserved human sciatic nerve.
This study aimed to describe the intraosseous blood supply of the distal radius and its clinical implications in distal radius fractures. Twelve adult wrists from fresh cadavers (six males, six females, 50-90 years of age, mean 68 years) were injected through the brachial artery with latex. Dissections were performed using magnifying loupes and hands were processed using the Spalteholz technique. The distal radius was supplied by three main vascular systems: epiphyseal, metaphyseal, and diaphyseal. The palmar epiphyseal vessels branched from the radial artery, palmar carpal arch, and anterior branch of the anterior interosseous artery. These vessels entered the bone through the radial styloid process at level of the Listers tubercle but palmar and sigmoid notch. The dorsal contribution to Listers tubercle is to the dorsal epiphyseal vessels. The intraosseous point of entry to the dorsal epiphyseal vessels was from the fourth and fifth extensor compartment arteries. In the metaphyseal area, we found numerous periosteal and cortical branches originating deep in the pronator quadratus and the anterior interosseous artery. These branches provided the main supply to the distal radius. Vessels perforated the bone and formed an anastomotic network. In the diaphyseal area, only the nutrient vessel provided intraosseous vascularity in the distal radius. Numerous metaphyseal-epiphyseal branches arise within the pronator quadratus and the anterior interosseous artery and course towards the distal radius. These branches may be fundamental to the healing of the distal radius fractures and make nonunion a rare complication.
Symmetrical cell division requires duplication of DNA and protein content to generate two daughter cells. Centrosomes also duplicate during cell division, but the mechanism controlling this process is incompletely understood. We describe an alternative splice form of SadB encoding a short SADB Ser/Thr kinase whose activity fluctuates during the cell cycle, localizes to centrosomes, and controls centrosome duplication. Reduction of endogenous SADB levels diminished centrosome numbers, whereas enhanced SADB expression induced centrosome amplification. SADB exerted this action through phosphorylation of gamma-tubulin on Ser 131, as expression of a phosphomimetic Ser 131-to-Asp gamma-tubulin mutant alone increased centrosome numbers, whereas non-phosphorylatable Ala 131-gamma-tubulin impaired centrosome duplication. We propose that SADB kinase activity controls centrosome homeostasis by regulating phosphorylation of gamma-tubulin.
Class I(A) phosphoinositide 3-kinase (PI3K) are enzymes comprised of a p85 regulatory and a p110 catalytic subunit that induce formation of 3-polyphosphoinositides, which activate numerous downstream targets. PI3K controls cell division. Of the 2 ubiquitous PI3K isoforms, alpha has selective action in cell growth and cell cycle entry, but no specific function in cell division has been described for beta. We report here a unique function for PI3Kbeta in the control of DNA replication. PI3Kbeta regulated DNA replication through kinase-dependent and kinase-independent mechanisms. PI3Kbeta was found in the nucleus, where it associated PKB. Modulation of PI3Kbeta activity altered the DNA replication rate by controlling proliferating cell nuclear antigen (PCNA) binding to chromatin and to DNA polymerase delta. PI3Kbeta exerted this action by regulating the nuclear activation of PKB in S phase, and in turn phosphorylation of PCNA negative regulator p21(Cip). Also, p110beta associated with PCNA and controlled PCNA loading onto chromatin in a kinase-independent manner. These results show a selective function of PI3Kbeta in the control of DNA replication.
A large body of evidence supports a correlation between inflammation and cancer, although the molecular mechanisms that govern this process are incompletely understood. Phosphatidylinositol 3-kinase (PI3K) is an enzyme that regulates the immune response and contributes to cell transformation in several tumor types. Here, we address the role of the PI3Kgamma isoform in inflammatory bowel disease and in the development of colitis-associated cancer.
CD28 is a receptor expressed on T cells that regulates their differentiation after antigen stimulation to long-term-survival memory T cells. CD28 enhances T-cell receptor signals and reduces expression of CBL ubiquitin ligases, which negatively control T-cell activation. In the absence of CD28 ligation during the primary stimulation, CBL levels remain high and T cells fail to mount an efficient secondary response. CD28 associates with p85alpha, one of the regulatory subunits of phosphoinositide-3-kinase (PI3K), but the relevance of this interaction is debated. We examined here the contribution of the other ubiquitous PI3K regulatory subunit, p85beta, in CD28 function. We describe that p85beta bound to CD28 and to CBL with greater affinity than p85alpha. Moreover, deletion of p85beta impaired CD28-induced intracellular events, including c-CBL and CBL-b down-regulation as well as PI3K pathway activation. This resulted in defective differentiation of activated T cells, which failed to exhibit an efficient secondary immune response. Considering that p85beta-deficient T cells fail in recall responses and that p85beta binds to and regulates CD28 signals, the presented observations suggest the involvement of p85beta in CD28-mediated activation and differentiation of antigen-stimulated T cells.
Distances from brachial plexus to the coracoid process and the pleura are critical for performing infraclavicular block. We evaluated the influence of arm abduction on the position of the neurovascular bundle relative to the skin, to the coracoid process and to the pleura using ultrasonography.
Genomic integrity is preserved by the action of protein complexes that control DNA homeostasis. These include the sliding clamps, trimeric protein rings that are arranged around DNA by clamp loaders. Replication factor C (RFC) is the clamp loader for proliferating cell nuclear antigen, which acts on DNA replication. Other processes that require mobile contact of proteins with DNA use alternative RFC complexes that exchange RFC1 for CTF18 or RAD17. Phosphoinositide 3-kinases (PI3K) are lipid kinases that generate 3-poly-phosphorylated-phosphoinositides at the plasma membrane following receptor stimulation. The two ubiquitous isoforms, PI3Kalpha and PI3Kbeta, have been extensively studied due to their involvement in cancer and nuclear PI3Kbeta has been found to regulate DNA replication and repair, processes controlled by molecular clamps. We studied here whether PI3Kbeta directly controls the process of molecular clamps loading. We show that PI3Kbeta associated with RFC1 and RFC1-like subunits. Only when in complex with PI3Kbeta, RFC1 bound to Ran GTPase and localized to the nucleus, suggesting that PI3Kbeta regulates RFC1 nuclear import. PI3Kbeta controlled not only RFC1- and RFC-RAD17 complexes, but also RFC-CTF18, in turn affecting CTF18-mediated chromatid cohesion. PI3Kbeta thus has a general function in genomic stability by controlling the localization and function of RFC complexes.
Class I(A) phosphoinositide 3-kinases (PI3K) are enzymes composed of a p85 regulatory and a p110 catalytic subunit that control formation of 3-poly-phosphoinositides (PIP(3)). The PI3K pathway regulates cell survival, migration, and division, and is mutated in approximately half of human tumors. For this reason, it is important to define the function of the ubiquitous PI3K subunits, p110? and p110?. Whereas p110? is activated at G1-phase entry and promotes protein synthesis and gene expression, p110? activity peaks in S phase and regulates DNA synthesis. PI3K activity also increases at the onset of mitosis, but the isoform activated is unknown; we have examined p110? and p110? function in mitosis. p110? was activated at mitosis entry and regulated early mitotic events, such as PIP(3) generation, prometaphase progression, and spindle orientation. In contrast, p110? was activated near metaphase and controlled dynein/dynactin and Aurora B activities in kinetochores, chromosome segregation, and optimal function of the spindle checkpoint. These results reveal a p110? function in preserving genomic stability during mitosis.
Hypermethylation of SOCS genes is associated with many human cancers, suggesting a role as tumor suppressors. As adaptor molecules for ubiquitin ligases, SOCS proteins modulate turnover of numerous target proteins. Few SOCS targets identified so far have a direct role in cell cycle progression; the mechanism by which SOCS regulate the cell cycle thus remains largely unknown. Here we show that SOCS1 overexpression inhibits in vitro and in vivo expansion of human melanoma cells, and that SOCS1 associates specifically with Cdh1, triggering its degradation by the proteasome. Cells therefore show a G1/S transition defect, as well as a secondary blockade in mitosis and accumulation of cells in metaphase. SOCS1 expression correlated with a reduction in cyclin D/E levels and an increase in the tumor suppressor p19, as well as the CDK inhibitor p53, explaining the G1/S transition defect. As a result of Cdh1 degradation, SOCS1-expressing cells accumulated cyclin B1 and securin, as well as apparently inactive Cdc20, in mitosis. Levels of the late mitotic Cdh1 substrate Aurora A did not change. These observations comprise a hitherto unreported mechanism of SOCS1 tumor suppression, suggesting this molecule as a candidate for the design of new therapeutic strategies for human melanoma.
PIK3R2 encodes a ubiquitous regulatory subunit (p85?) of PI3K, an enzyme that generates 3-polyphosphoinositides at the plasma membrane. PI3K activation triggers cell survival and migration. We found that p85? expression is elevated in breast and colon carcinomas and that its increased expression correlates with PI3K pathway activation and tumor progression. p85? expression induced moderate PIP(3) generation at the cell membrane and enhanced cell invasion. In accordance, genetic alteration of pik3r2 expression levels modulated tumor progression in vivo. Increased p85? expression thus represents a cellular strategy in cancer progression.
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