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Objective:To investigate the effect of galectin-3 (gal-3) on microglia polarization after subarachnoid hemorrhage (SAH).Methods:C57BL/6 male adult mice were used to induce SAH or sham operation models. Gal-3 siRNA or negative control siRNA was injected into the lateral ventricle 48 h before the model was induced. After 24 h of model preparation, the SAH score, neurological function score, brain water content, and Evans blue exudate were measured. Western blot analysis was used to detect the expressions of M1 phenotypic markers (inducible nitric oxide synthase [iNOS], CD11b, tumor necrosis factor [TNF]-α) and M2 phenotype markers (CD206, YM1/2, arginase-1 [Arg1]).Results:After using Gal-3 siRNA to inhibit Gal-3, the neurological function score significantly increased, while the SAH score, brain water content, and Evans blue exudate significantly decreased ( P<0.001). Western blot analysis showed that the expressions of M1 phenotypic markers (iNOS, CD11b and TNF-α) in microglia were significantly decreased after Gal-3 inhibition, while the expressions of M2 phenotypic markers (CD206, YM1/2 and Arg1) were significantly increased ( P<0.001). Conclusion:Inhibition of Gal-3 expression can alleviate the early brain injury after SAH, and its mechanism may be associated with regulating the polarization of microglia from M1 to M2 phenotype.
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Objective:To evaluate the effect of irisin on the alveolar macrophage polarization in a rat model of ventilator-induced lung injury (VILI).Methods:Thirty SPF healthy adult male Sprague-Dawley rats, aged 6-8 weeks, weighing 200-250 g, were divided into 3 groups ( n=10 each) using a random number table method: control group (group C), VILI group (group V) and irisin group (group I). The rats were mechanically ventilation (tidal volume 20 ml/kg, respiratory rate 80 times/min, inhaled oxygen concentration 21%, inspiratory/expiratory ratio 1∶2, positive end-expiratory pressure 0) for 4 h to develop VILI model.Group C kept spontaneous breathing for 4 h. Irisin 1 μg/kg was injected via the tail vein at 30 min before tracheal intubation in group I, while the equal volume of normal saline was given instead in the other groups.The rats were sacrificed at 4 h of mechanical ventilation, the lung tissues were removed for examination of pathological changes which were scored and for determination of wet to dry weight ratio (W/D ratio), and bronchoalveolar lavage fluid (BALF) was collected for determination of concentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and IL-10 (by enzyme-linked immunosorbent assay), expression of inducible nitric oxide synthase (iNOS), argininase 1 (Arg-1), and phosphorylated nuclear factor kappa B (p-NF-κB) p65 and p-NF-κB p50 in alveolar macrophages (by Western blot), and percentage of M1 and M2 alveolar macrophages and M1/M2 ratio (by flow cytometry). Results:Compared with group C, the W/D ratio, lung injury score, and concentrations of IL-6, TNF-α and IL-10 in BALF were significantly increased, the expression of iNOS, Arg-1, p-NF-κB p65 and p-NF-κB p50 was up-regulated, and the percentage of M1 and M2 alveolar macrophages and M1/M2 ratio were increased in group V and group I ( P<0.05). Compared with group V, the W/D ratio, lung injury score, and concentrations of IL-6 and TNF-α in BALF were significantly decreased, the expression of iNOS and p-NF-κB p65 was down-regulated, the percentage of M1 alveolar macrophages and M1/M2 ratio were decreased ( P<0.05), and no significant change was found in levels of IL-10 and Arg-1 in BALF, percentage of M2 alveolar macrophages and expression of p-NF-κB p50 in group I ( P>0.05). Conclusions:The mechanism by which irisin reduces VILI may be related to inhibition of NF-κB signaling pathway activation and reduction of alveolar macrophage polarization to M1 phenotype in rats.
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Background The atypical cadherin Celsr3, which belongs to the core planar cell polarity group, orchestratesaxonal guidance and network wiring. Previous work using regional inactivation of Celsr3 in forebrain showedthat Celsr3 is widely involved in hippocampal maturation and connectivity. However, inactivation in the wholeforebrain does not provide sufficient specificity to address the function of Celsr3 in detail.Method We studied the Celsr3|Emx1 mouse mutant model, in which Celsr3 is selectively inactivated inhippocampal projection neurons, but not in entorhinal cortex, basal ganglia and interneurons.Result In that mutant, the hippocampal cytoarchitecture was almost normal. Inactivation of Celsr3 inprojection neurons perturbed intrinsic hippocampal wiring. Consistent with wiring defects, Celsr3|Emx1mutant mice showed impaired learning and memory, and were less anxiety-prone than control mice.Conclusion Celsr3|Emx1 mutant mice provide a simple way to study the consequences of defectivehippocampal wiring in absence of drastic structural anomalies.
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@#Regarded as a complex biological process, lens development involves a range of signal molecules and their crosstalk networks. Recently,the role of planar cell polarity(PCP)signaling pathway in lens development has attracted increasing attention. It has been reported that PCP is critical for lens morphology and transparency maintaining. The studies performed on PCP serve to provide guidelines on how to optimize the morphology of regenerated lens. This is thought as presenting an effective therapy for infant cataract from a clinical perspective. This article will give a comprehensive review of the role of PCP signaling pathways in the lens development.
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The polarity of ameloblasts and odontoblasts is crucial for their differentiation and function. Polarity-related molecules play an important role in this process. This review summarizes the process of polarity formation of ameloblasts and odontoblasts and their related regulators.
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Ameloblasts , Cell Differentiation , OdontoblastsABSTRACT
As a member of the ERM (Ezrin/Radixin/Moesin) protein family, Ezrin is widely distributed in the body. Ezrin acts as a "scaffold" participating in anchorage and interacting between plasma membrane and cytoskeleton. Its special subcel-lular localization is critical for many complex cell processes. Increasing evidence suggests that the abnormal expression, phosphorylation and localization of Ezrin would affect tumor progression. The influence of Ezrin on the morphology of tumor cells during metastasis has gradually attracted the attention of researchers. Further investigations that focus on the mechanism of Ezrin' s influence on different stages of tumor metastasis will be gradually elucidated. In this article, we review the biological functions of Ezrin and its research progress in tumor metastasis, and explain the mechanism of Ezrin-mediated tumor metastasis. It is proposed that strategies targeting Ezrin for tumor metastasis treatment are a promising way to achieve great success in clinic.
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Objective: To clarify the role of discs large homolog 5 (DLG5) in the diagnosis and prognosis of renal clear cell carcinoma (ccRCC) by studying the expression of DLG5 in the clinical tissue of ccRCC. Methods: DLG5 expression in ccRCC tissues and normal renal tissue was measured by using the Cancer Genome Atlas (TCGA) Database and Gene Expression Omnibus (GEO) Database. The correlation of DLG5 expression with the prognosis and clinicopathological parameters of ccRCC was analyzed by LinkedOmics and GEPIA. The interactions protein network of DLG5 was predicted by String-DB. Results: Compared with that of the normal kidney tissues, DLG5 expression was significantly upregulated in the ccRCC tissues (P<0.05). The high DLG5 expression was an independent prognostic factor affecting the overall survival rate of ccRCC based on TCGA (P=2.997×10-5). Furthermore, DLG5 expression had a positive correlation with the TNM stage, ethnicity, tumor purity, year-to-birth, PCNA (P=1.1×10-6, R=0.19), and RAD1 (P=5.7×10-6, R=0.18) expression of ccRCC. Conclusion: In ccRCC, the high expression of DLG5 is a significant index of poor prognosis. Therefore, DLG5 can be a potential biomarker for predicting the metastasis, recurrence and prognosis of the patients.
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Objective To investigate the effect of different fluid shear stress (FSS) on the regulation of planar cell polarity (PCP) signaling, and further to explore the relationship among FSS, PCP signaling pathway and ciliogenesis. Methods The hydrodynamic cell model of adjustable FSS was established. qPCR and immunofluorescence were used to detect the mRNA expression of PCP signaling pathway core protein Dvl2 and cilia assembly protein IFT88, cell targeting and co-localization under different FSS. Western blot (WB) was used to detect the protein expression of Dvl2 at 18 h under different FSS. Results The qPCR result showed that compared with 1.5 Pa FSS, under 0.1 Pa FSS, the mRNA expression of Dvl2 was higher at 6 h and 18 h (P＜0.05), significantly higher at 12 h (P＜0.01); the mRNA expression of IFT88 was significantly higher at 18 h (P＜0.01). The WB result showed that compared with 0 h, under 0.1 Pa FSS, the protein expression of Dvl2 was higher at 18 h (P＜0.05), significantly lower under 1.5 Pa FSS (P＜0.01); compared with 1.5 Pa FSS, the protein expression of Dvl2 was higher at 18 h under 0.1 Pa FSS (P＜0.05). The immunofluorescence result showed that the positive expression of Dvl2 increased with the loading time on FSS increasing, and gradually aggregated at a point around the nucleus; the positive expression of IFT88 was gradually transferred from the nucleus to the cytoplasm and aggregated at a point under 0.1 Pa FSS, and gradually decreased and depolymerized under 1.5 Pa FSS. Protein Dvl2 and IFT88 were located in the same position in cells under 0.1 Pa FSS and before 18 h under 1.5 Pa FSS, and colocalization of proteins Dvl2 and IFT88 was not observed after 18 h under 1.5 Pa FSS due to IFT88 depolymerization. Conclusions Laminar FSS played an inhibition on the transduction of PCP signaling pathway and a hindrance on the process of ciliogenesis, while low FSS played a promotion on the transduction. PCP signaling pathway might regulate FSS-induced ciliogenesis by Dvl2.
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Objective:To study the expressions of cell polarity related proteins CDC42 and PAR3 during tooth germ development in the mice,and to discuss their possible roles during tooth development in the mice.Methods:The whole heads were obtained from the mouse embryo on the days 13.5,14.5,16.5 and 18.5 (E13.5,E14.5,E16.5 and E18.5) and the mice on the postnatal days 1 (PN1) and 5 (PN5).The tissues were fixed in paraformaldehyde,decalcified,dehydrated,embedded in paraffin,and sectioned.The histology of tooth germ was observed by HE staining.The expressions of CDC42 and PAR3 during tooth germ development were detected by immunohistochemistry staining.Results:The HE staining results showed that E13.5,E14.5,E16.5 and E18.5were the bud stage,the cap stage,the early and the late bell stage of tooth germ development,respectively;the tooth germ of PN1 mice showed the matured odontoblasts and ameloblasts;the tooth germ of PN5 mice showed the completed tooth crown development.The immunohistochemistry staining results showed that CDC42 expressed in the tooth germ of the mice at E13.5,E14.5 and E16.5;the CDC42 expression at E 18.5 was reduced compared with E13.5,E14.5 and E16.5;CDC42 mainly expressed in the odontoblasts and ameloblasts of the tooth germ of the mice at PN1 and PN5;PAR3 weakly expressed in the tooth germ of the mice at E13.5 and E14.5,and it was increased at E16.5 and E18.5.At PN1 and PN5,the expressions of PAR3 were decreased compared with E18.5.Conclusion:CDC42 and PAR3 partieipat in the mouse tooth development;during the early stage of tooth germ development,they may be involved in the proliferation and migration of mouse dental germ;during the late stage,CD42 and PAR3 may be involved in the differentiation of the odontoblasts and the ameloblasts,especially in the establishment and maintenance of cell polarity.
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Objective To investigate the role of β-catenin,the core protein of canonical Wnt/β-catenin signaling,in the inner-ear development and polarity regulation.Methods β-catenin was conditionally deleted from precursor cells of inner-ear sensory epithelium (Sox2-positive cells) in embryonic mice.Morphological changes of the inner ear were observed.Immunofluorescence staining was performed to basilar membranes,utricles and saccules to observe the hair-cell changes in arrangement and polarity.Results Compared with the control group,knock-out of β-catenin in Sox2-positive cells resulted in smaller otic vesicles,cochleas and vestibules,and fewer hair cells (HCs) in vestibular sensory epithelium (P＜0.01).Stereocilium showed misorientation and kinocillia had a change in location and quantity in the cochlea.Scattered misorented HCs were also observed in the vestibule.Conclusions β-catenin is crucial for the development of inner ear and polarity manipulation of HCs in mice.The canonical Wnt/β-catenin signaling may be involved in the regulation of cochlea extension and planar cell polarity (PCP) of inner ear,which is known to be controlled by non-canonical Wnt/PCP signaling.
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Background@#Valproic acid (VPA) exposure during pregnancy has been proven to contribute to congenital heart disease (CHD). Our previous findings implied that disruption of planar cell polarity (PCP) signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase (HDAC) inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes (Vangl2/Scrib/Rac1), subsequently screening out the specific HDACs regulating PCP pathway.@*Methods@#VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day 10.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells (undifferentiated rat cardiomyoblasts) were transfected with Hdac1/2/3 specific small interfering RNA (siRNA). Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Rac1 mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric assay.@*Results@#VPA could induce CHD (P 0.05); VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity (P 0.05).@*Conclusion@#VPA could inhibit Hdac1/2/3, Vangl2/Scrib, or total Hdac activity both in vitro and in vivo and Hdac3 might participate in the process of VPA-induced cardiac developmental anomalies.
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Animals , Female , Mice , Pregnancy , Rats , Cell Polarity , Enzyme Inhibitors , Fetal Heart , Embryology , Heart Defects, Congenital , Histone Deacetylase Inhibitors , Histone Deacetylases , Physiology , Mice, Inbred C57BL , Nerve Tissue Proteins , Transfection , Valproic AcidABSTRACT
Objective: To study the expressions of cell polarity related proteins CDC42 and PAR3 during tooth germ development in the mice, and to discuss their possible roles during tooth development in the mice. Methods: The whole heads were obtained from the mouse embryo on the days 13. 5, 14. 5, 16. 5 and 18. 5 (E13. 5, E14. 5, E16. 5 and E18. 5) and the mice on the postnatal days 1 (PN1) and 5 (PN5). The tissues were fixed in paraformaldehyde, decalcified, dehydrated, embedded in paraffin, and sectioned. The histology of tooth germ was observed by HE staining. The expressions of CDC42 and PAR3 during tooth germ development were detected by immunohistochemistry staining. Results: The HE staining results showed that E13. 5, E14. 5, E16. 5 and E18. 5 were the bud stage, the cap stage, the early and the late bell stage of tooth germ development, respectively; the tooth germ of PN1 mice showed the matured odontoblasts and ameloblasts; the tooth germ of PN5 mice showed the completed tooth crown development. The immunohistochemistry staining results showed that CDC42 expressed in the tooth germ of the mice at E13. 5, E14. 5 and E16. 5; the CDC42 expression at E 18. 5 was reduced compared with E13. 5, E14. 5 and E16. 5; CDC42 mainly expressed in the odontoblasts and ameloblasts of the tooth germ of the mice at PN1 and PN5; PAR3 weakly expressed in the tooth germ of the mice at E13. 5 and E14. 5, and it was increased at E16. 5 and E18. 5. At PN1 and PN5, the expressions of PAR3 were decreased compared with E18. 5. Conclusion: CDC42 and PAR3 participat in the mouse tooth development; during the early stage of tooth germ development, they may be involved in the proliferation and migration of mouse dental germ; during the late stage, CD42 and PAR3 may be involved in the differentiation of the odontoblasts and the ameloblasts, especially in the establishment and maintenance of cell polarity.
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OBJECTIVE@#This study aims to investigate whether dexamethasone (DEX) can down-regulate the PAR complex and disrupt the cell polarity in the palatal epithelium during palatal fusion.@*METHODS@#Pregnant rats were randomly divided into control and DEX groups, which were injected intraperitoneally with 0.9% sodium chloride (0.1 mL) and DEX (6 mg·kg ⁻¹), respectively, every day from E10 to E12. The palatal epithelial morphology was observed using hematoxylin and eosin staining and scanning electron microscopy. Immunofluorescence staining, Western Blot analysis, and real-time polymerase chain reaction were performed to detect the expression of PAR3, PAR6, and aPKC.@*RESULTS@#The incidence of cleft palate in DEX group (46.15%) was significantly higher than that in control group (3.92%), and the difference was statistically significant (χ2=24.335, P=0.00). DEX can also retard the growth of the palatal shelves and the short palatal shelves. The morphology and arrangement of MEE cells changed from polarized bilayer cells to nonpolarized monolayer ones. Additionally, the spherical structure decreased, which caused the cleft palate. PAR3 and PAR6 were only detected in the palatal epithelium, and aPKC was expressed in the palatal epithelium and mesenchyme. DEX can reduce the expression levels of PAR3, PAR6, and aPKC in the protein and gene levels.@*CONCLUSIONS@#DEX can down-regulate the complex gene expression in the MEE cells, thereby destroying the cell polarity and causing cleft palate.
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Animals , Female , Pregnancy , Rats , Carrier Proteins , Physiology , Cell Polarity , Cleft Palate , Dexamethasone , Pharmacology , Epithelial Cells , Glucocorticoids , Pharmacology , PalateABSTRACT
Microglia play a crucial role in inflammation after cerebral ischemia.A large number of studies have shown that microglia are highly plastic cells that can assume different phenotypes and functions in response to specific microenvironmental signals.Microglia can be polarized into the classically activated proinflammatory M1 phenotype or the alternatively activated anti-inflammatory M2 phenotype,and play different roles in ischemic injury.Irnhibiting M1 while stimulating M2 may be a new approach for the treatment of ischemic stroke.
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In recent years, three-dimensional (3D) in vitro cell culture models have earned great attention, especiallyin the field of human cancer disease modelling research as they provide a promising alternative towardsthe conventional two-dimensional (2D) monolayer culture of cells with improved tissue organization. In2D cell culture systems, the complexity of cells on a planar surface does not accurately reflects the invivo cellular microenvironment. Cells propagated in 3D cell culture model, on the other hand, exhibitphysiologically relevant cell-to-cell interactions and cell-to-extracellular matrix (ECM) interactions,important in maintaining a normal homeostasis and specificity of tissues. This review gives an overviewon 2D models and their limitations, followed by 3D cell culture models, their advantages, drawbacks andchallenges in present perspectives. The review also highlights the dissimilarities of 2D and 3D modelsand the applicability of 3D models in current cancer research.
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Cell polarity is a common feature of many different types of cells,and it is essential to the normal differentiation and function of cells. Partitioning defective 6( PAR6)gene encodes PAR6 protein, which is crucial to asymmetric cell division and polarized growth. PAR6 protein as a member of the PAR6 polarity complex,affects the synthetic of centrosome and protein recruitment to the centrosome. The abnormal number of centrosomal and the loss of cell polarity may eventually lead to the occurrence of tumor.
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Inflammation plays a key role in the secondary brain injury after cerebral ischemia,in which microglia activation and polarization play important roles.This article reviews the roles of microglia in inflammation and the molecular mechanisms of microglia activation and polarization after cerebral ischemia.
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BACKGROUND: Adult neural stem cells have the potential for self-renewal and differentiation into multiple cell lineages via symmetric or asymmetric cell division. Preso1 is a recently identified protein involved in the formation of dendritic spines and the promotion of axonal growth in developing neurons. Preso1 can also bind to cell polarity proteins, suggesting a potential role for Preso1 in asymmetric cell division. METHODS: To investigate the distribution of Preso1, we performed immunohistochemistry with adult mouse brain slice. Also, polarized distribution of Preso1 was assessed by immunocytochemistry in cultured neural stem cells. RESULTS: Immunoreactivity for Preso1 (Preso1-IR) was strong in the rostral migratory stream and subventricular zone, where proliferating transit-amplifying cells and neuroblasts are prevalent. In cultured neural stem cells, Preso1-IR was unequally distributed in the cell cytosol. We also observed the distribution of Preso1 in the subgranular zone of the hippocampal dentate gyrus, another neurogenic region in the adult brain. Interestingly, Preso1-IR was transiently observed in the nuclei of doublecortin-expressing neuroblasts immediately after asymmetric cell division. CONCLUSION: Our study demonstrated that Preso1 is asymmetrically distributed in the cytosol and nuclei of neural stem/progenitor cells in the adult brain, and may play a significant role in cell differentiation via association with cell polarity machinery.
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Adult , Animals , Humans , Mice , Asymmetric Cell Division , Axons , Brain , Cell Differentiation , Cell Lineage , Cell Polarity , Cytosol , Dendritic Spines , Dentate Gyrus , Immunohistochemistry , Neural Stem Cells , Neurons , RiversABSTRACT
The epithelial-mesenchymal transition (EMT) is a biological phenomenon responsible for the formation of different tissues and organs during normal metazoan development. Because of the connection of the EMT with the pathogenesis of certain diseases, such as cancer, the attention of the scientific community has been directed towards the search for and identification of effective therapeutic targets. These targets include signal transduction in cancerous stem cells and the use of microRNAs, which would inhibit EMT-associated phenotypic changes and tumoral progression. In an attempt to compile relevant and current information, this work addresses concepts that define the EMT and the advances in this field. The wealth of knowledge gained from areas such as the loss of cell polarity and intracellular adhesion complexes, the signaling pathways implicated, microRNA participation in this process, and stemness acquisition in embryonic and cancerous cells, all of which allow for the visualization of promising perspectives, particularly, methods for targeting advanced malignancies, are presented herein.
La transición epitelio-mesenquimática (TEM) es el fenómeno biológico responsable de la formación de los diferentes tejidos y órganos durante el desarrollo normal de los organismos metazoarios. En razón de su conexión con la patogénesis de ciertas enfermedades como el cáncer, la atención de la comunidad científica se ha redireccionado hacia la búsqueda e identificación de blancos terapéuticos efectivos, como la transducción de señales de las células madre cancerosas o la utilización de microARNs, que permitirían bloquear los cambios fenotípicos asociados con la TEM y, por ende, la progresión tumoral. En un intento por recopilar información relevante y actualizada, el presente trabajo aborda conceptos que definen a la TEM y avances alcanzados en este campo. El acervo de conocimiento obtenido en aspectos como pérdida de la polaridad celular y de los complejos de adhesión intercelular, vías de señalización implicadas y participación de los microARNs en el proceso, así como adquisición de stemness o troncalidad, tanto en células embrionarias como cancerosas, hace posible visualizar perspectivas promisorias, en especial en lo que se refiere a las terapias contra las malignidades de alto grado.
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Animals , Humans , Antineoplastic Agents/pharmacology , Epithelial-Mesenchymal Transition , Molecular Targeted Therapy , Neoplasms/therapy , Antineoplastic Agents/therapeutic use , Cell Adhesion , Cell Differentiation , Cell Movement , Cell Polarity , Cell Transformation, Neoplastic , Cell Adhesion Molecules/physiology , Disease Progression , Embryonic Development , Epithelial-Mesenchymal Transition/drug effects , Epithelial-Mesenchymal Transition/physiology , Fibrosis , Intracellular Signaling Peptides and Proteins/physiology , MicroRNAs/physiology , Neoplasm Proteins/physiology , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , RNA, Neoplasm/physiology , Signal Transduction/drug effects , Signal Transduction/physiologyABSTRACT
GIPC1, GIPC2 and GIPC3 consist of GIPC homology 1 (GH1) domain, PDZ domain and GH2 domain. The regions around the GH1 and GH2 domains of GIPC1 are involved in dimerization and interaction with myosin VI (MYO6), respectively. The PDZ domain of GIPC1 is involved in interactions with transmembrane proteins [IGF1R, NTRK1, ADRB1, DRD2, TGFbetaR3 (transforming growth factorbeta receptor type III), SDC4, SEMA4C, LRP1, NRP1, GLUT1, integrin alpha5 and VANGL2], cytosolic signaling regulators (APPL1 and RGS19) and viral proteins (HBc and HPV-18 E6). GIPC1 is an adaptor protein with dimerizing ability that loads PDZ ligands as cargoes for MYO6-dependent endosomal trafficking. GIPC1 is required for cell-surface expression of IGF1R and TGFbetaR3. GIPC1 is also required for integrin recycling during cell migration, angiogenesis and cytokinesis. On early endosomes, GIPC1 assembles receptor tyrosine kinases (RTKs) and APPL1 for activation of PI3K-AKT signaling, and G protein-coupled receptors (GPCRs) and RGS19 for attenuation of inhibitory Galpha signaling. GIPC1 upregulation in breast, ovarian and pancreatic cancers promotes tumor proliferation and invasion, whereas GIPC1 downregulation in cervical cancer with human papillomavirus type 18 infection leads to resistance to cytostatic transforming growth factorbeta signaling. GIPC2 is downregulated in acute lymphocytic leukemia owing to epigenetic silencing, while Gipc2 is upregulated in estrogen-induced mammary tumors. Somatic mutations of GIPC2 occur in malignant melanoma, and colorectal and ovarian cancers. Germ-line mutations of the GIPC3 or MYO6 gene cause nonsyndromic hearing loss. As GIPC proteins are involved in trafficking, signaling and recycling of RTKs, GPCRs, integrins and other transmembrane proteins, dysregulation of GIPCs results in human pathologies, such as cancer and hereditary deafness.