Regulation of PtdIns(3,4,5)<i>P</i>3/Akt signalling by inositol polyphosphate 5-phosphatases

Eramo, Matthew J; Mitchell, Christina A.

doi:10.1042/bst20150214

Cited by 55 publications

(50 citation statements)

References 117 publications

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“…PI3K activation is initiated by the engagement of receptor tyrosine kinases (RTKs) to extracellular growth factors, which recruits PI3K to plasma membrane-anchored receptors and results in the conversion of PI3K phosphorylates phosphatidylinositol(4)bisphosphate (PI(4)P) and phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2) to phosphatidylinositol (3,4)bisphosphate (PI(3,4)P2) and phosphatidylinositol (3,4,5)trisphosphate (PI(3,4,5)P3). PI (3,4)P2 and PI (3,4,5)P3 subsequently bind to and activate multiple downstream effectors [2]. Among them, Akt is an important effector protein kinase which is highly activated in nearly 80% of gastric cancers (GCs), and its activation may serve as a biomarker for the diagnosis of GC and as a molecular target for treatment [3].…”

Section: Introductionmentioning

confidence: 99%

IQGAP2 Inhibits Migration and Invasion of Gastric Cancer Cells via Elevating SHIP2 Phosphatase Activity

Shao

Ren

et al. 2020

IJMS

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Previous studies have shown reduced expression of Src homology 2-containing inositol 5-phosphatase 2 (SHIP2) and its tumor-suppressive role in gastric cancer (GC). However, the precise role of SHIP2 in the migration and invasion of GC cells remains unclear. Here, an IQ motif containing the GTPase-activating protein 2 (IQGAP2) as a SHIP2 binding partner, was screened and identified by co-immunoprecipitation and mass spectrometry studies. While IQGAP2 ubiquitously expressed in GC cells, IQGAP2 and SHIP2 co-localized in the cytoplasm of GC cells, and this physical association was confirmed by the binding of IQGAP2 to PRD and SAM domains of SHIP2. The knockdown of either SHIP2 or IQGAP2 promoted cell migration and invasion by inhibiting SHIP2 phosphatase activity, activating Akt and subsequently increasing epithelial–mesenchymal transition (EMT). Furthermore, knockdown of IQGAP2 in SHIP2-overexpressing GC cells reversed the inhibition of cell migration and invasion by SHIP2 induction, which was associated with the suppression of elevated SHIP2 phosphatase activity. Moreover, the deletion of PRD and SAM domains of SHIP2 abrogated the interaction and restored cell migration and invasion. Collectively, these results indicate that IQGAP2 interacts with SHIP2, leading to the increment of SHIP2 phosphatase activity, and thereby inhibiting the migration and invasion of GC cells via the inactivation of Akt and reduction in EMT.

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Section: Introductionmentioning

confidence: 99%

IQGAP2 Inhibits Migration and Invasion of Gastric Cancer Cells via Elevating SHIP2 Phosphatase Activity

Shao

Ren

et al. 2020

IJMS

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“…Src Homology 2‐containing Inositol Phosphatase‐1 (SHIP‐1) controls the intracellular levels of PI3K product PIP3 and functions as a negative regulator of cytokine and immune receptor signaling . Deletion of the SHIP‐1 gene in mice leads to an immunological phenotype with overproduction of pro‐inflammatory cytokines, activation of myeloid cells, and severe inflammation in the lung .…”

Section: Introductionmentioning

confidence: 99%

“…Src Homology 2-containing Inositol Phosphatase-1 (SHIP-1) controls the intracellular levels of PI3K product PIP3 and functions as a negative regulator of cytokine and immune receptor signaling. 1,2 Deletion of the SHIP-1 gene in mice leads to an immunological phenotype with overproduction of pro-inflammatory cytokines, activation of myeloid cells, and severe inflammation in the lung. 3,4 Previous studies by our laboratory and others showed that whole-body SHIP-1 KO mice developed a type 2 like severe lung inflammation and lung fibrosis 5,6 These studies demonstrated that SHIP-1 plays an important role in maintaining lung homeostasis.…”

Section: Introductionmentioning

confidence: 99%

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

Tang

Mao

et al. 2019

FASEB j.

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Src Homology 2‐containing Inositol Phosphatase‐1 (SHIP‐1) is a target of miR‐155, a pro‐inflammatory factor. Deletion of the SHIP‐1 gene in mice caused spontaneous lung inflammation and fibrosis. However, the role and function of endothelial miR‐155 and SHIP‐1 in lung fibrosis remain unknown. Using whole‐body miR‐155 knockout mice and endothelial cell–specific conditional miR‐155 (VEC‐Cre‐miR‐155 or VEC‐miR‐155) or SHIP‐1 (VEC‐SHIP‐1) knockout mice, we assessed endothelial‐mesenchymal transition (EndoMT) and fibrotic responses in bleomycin (BLM) induced lung fibrosis models. Primary mouse lung endothelial cells (MLEC) and human umbilical vein endothelial cells (HUVEC) with SHIP‐1 knockdown were analyzed in TGF‐β1 or BLM, respectively, induced fibrotic responses. Fibrosis and EndoMT were significantly reduced in miR‐155KO mice and changes in EndoMT markers in MLEC after TGF‐β1 stimulation confirmed the in vivo findings. Furthermore, lung fibrosis and EndoMT responses were reduced in VEC‐miR‐155 mice but significantly enhanced in VEC‐SHIP‐1 mice after BLM challenge. SHIP‐1 knockdown in HUVEC cells resulted in enhanced EndoMT induced by BLM. Meanwhile, these changes involved the PI3K/AKT, JAK/STAT3, and SMAD/STAT signaling pathways. These studies demonstrate that endothelial miR‐155 plays an important role in fibrotic responses in the lung through EndoMT. Endothelial SHIP‐1 is essential in controlling fibrotic responses and SHIP‐1 is a target of miR‐155. Endothelial cells are an integral part in lung fibrosis.

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“…Since WT knobs are enriched with PI(3,4)P2 it may hypothetically serve as a product of PIP3 hydrolysis by INPP5E or phosphorylation substrate for PI5K, a process typical for endosomal membranes (Posor et al, 2013). INPP5E in the medulloblastoma PC is mostly involved in converting PIP3 into PI(3,4)P2 (Eramo and Mitchell, 2016). However, the canonical route of PIP3 synthesis is via recruiting of class I and II PI3K occurring mostly during tyrosine kinase receptor activation during proliferation (Hawkins and Stephens, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…One important consideration comparing PC and olfactory cilia in mature OSNs is that ciliogenesis of the PC is typically induced in cell culture by serum starvation or during embryogenesis by growth factors targeting Shh and/or tyrosine kinase receptor PI3K/PIP3/Akt pathways (Eramo and Mitchell, 2016). Probably, at the terminal developmental stage OSNs lack input from Hedgehog signaling negatively regulated by PIP2 in the PC through TULP-3 and Gpr161 (Mukhopadhyay et al, 2010;Chávez et al, 2015;Wrighton, 2015;Xu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

Ukhanov

Uytingco

Green

et al. 2018

Preprint

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Ciliopathies manifested in part by a dysfunction of several phosphoinositide 5'phosphatases constitute Lowes, Dent disease 2 and Joubert syndromes through critical involvement of properly functioning primary cilia (PC). We showed that deletion of INPP5E under the control of OMP-Cre in mature mouse olfactory sensory neurons (OSNs) led to a dramatic redistribution of PI(4,5)P2 (PIP2) in cilia, significant reduction of PI(3,4)P2 and enrichment of PI(3,4,5)P3 in knobs.Redistribution of the phospholipids accompanied marked elongation of cilia in INPP5E-OMP knockout (KO) OSNs. Such a dramatic remodeling of phospholipid composition however did not affect other integral membrane lipids (cholesterol, sphingomyelin, glycosylated phosphaditylinositol, phosphatidylserine). Proteins known to bind with high affinity PIP2 entered the cilia of the KO OSNs. Loss of INPP5E did not affect ciliary localization of endogenous olfactory receptor M71/M72 or distribution and movement of IFT122 particles implicating independent of phospholipids mechanism of retrograde protein transport in cilia of mature OSNs. Net odor sensitivity and response magnitude as measured by EOG was not affected by the mutation.However, odor adaptation in the KO mouse was significantly impaired resulting in less efficient recovery and altered inactivation kinetics of the odor response at the EOG and single-cell level.These findings implicate phosphoinositide-dependent regulation of active Ca 2+ extrusion in OSNs whereby controlling the rate of sensory adaptation. Significance statementCurrently there are little if any available treatment to cure congenital ciliopathies. This is in part due to lack of basic knowledge of cilia biology. Olfactory cilia as well as primary cilia appear to be a phospholipid privileged organelle distinct from the rest of plasma membrane albeit sharing its continuity. We characterized distribution of several critically important for cell biology phospholipids and showed that their balance, especially of PIP2, is disrupted in Joubert syndrome animal model and has functional implications. Virally assisted delivery of wild type INPP5E to the mutant OSNs was able to restore localization of PIP2 and rescued impaired response to odor.

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Regulation of PtdIns(3,4,5)P3/Akt signalling by inositol polyphosphate 5-phosphatases

Cited by 55 publications

References 117 publications

IQGAP2 Inhibits Migration and Invasion of Gastric Cancer Cells via Elevating SHIP2 Phosphatase Activity

IQGAP2 Inhibits Migration and Invasion of Gastric Cancer Cells via Elevating SHIP2 Phosphatase Activity

SHIP‐1, a target of miR‐155, regulates endothelial cell responses in lung fibrosis

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

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