Regulation of IGF-1/PI3K/Akt signalling by the phosphoinositide phosphatase pharbin

Wang, Feng; Ijuin, Takeshi; Itoh, Toshiki; Takenawa, Tadaomi

doi:10.1093/jb/mvr037

Cited by 15 publications

(16 citation statements)

References 36 publications

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“…Further, we confirmed that INPP5E siRNAs did not impact MAD2 (data not shown), whose transcript is sensitive to nonspecific siRNA silencing (34). INPP5E overexpression caused cellular toxicity, as described before (references 6 and 35 and data not shown). Consistent with its role in cell division, INPP5E accumulates as cells progress through interphase toward mitosis (Fig.…”

Section: Discussionsupporting

confidence: 69%

INPP5E Preserves Genomic Stability through Regulation of Mitosis

Potchanant

Cerabona

Abdul‐Sater

et al. 2017

Molecular and Cellular Biology

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The partially understood phosphoinositide signaling cascade regulates multiple aspects of cellular metabolism. Previous studies revealed that INPP5E, the inositol polyphosphate-5-phosphatase that is mutated in the developmental disorders Joubert and MORM syndromes, is essential for the function of the primary cilium and maintenance of phosphoinositide balance in nondividing cells. Here, we report that INPP5E further contributes to cellular homeostasis by regulating cell division. We found that silencing or genetic knockout of INPP5E in human and murine cells impairs the spindle assembly checkpoint, centrosome and spindle function, and maintenance of chromosomal integrity. Consistent with a cell cycle regulatory role, we found that INPP5E expression is cell cycle dependent, peaking at mitotic entry. INPP5E localizes to centrosomes, chromosomes, and kinetochores in early mitosis and shuttles to the midzone spindle at mitotic exit. Our findings identify the previously unknown, essential role of INPP5E in mitosis and prevention of aneuploidy, providing a new perspective on the function of this phosphoinositide phosphatase in health and development.

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Section: Discussionsupporting

confidence: 69%

INPP5E Preserves Genomic Stability through Regulation of Mitosis

Potchanant

Cerabona

Abdul‐Sater

et al. 2017

Molecular and Cellular Biology

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“…INPP5E dephosphorylates at the 5-position PtdIns(3,4,5)P 3 ( 159,177,178 ), PtdIns(4,5)P 2 ( 159,178,179 ), and PtdIns(3,5)P 2 ( 177 ) in vitro. In contrast, other reports have suggested that neither PtdIns(4,5) P 2 ( 177 ) nor PtdIns(3,5)P 2 ( 178 ) are substrates for INPP5E in vitro. Furthermore, it has been reported that Ins(1,4,5) P 3 and Ins(1,3,4,5)P 4 can be dephosphorylated by INPP5E ( 179 ); however, other studies have shown they are not substrates ( 159,177 ).…”

Section: Phosphoinositide 4-phosphatase Activities and Cancermentioning

confidence: 99%

“…INPP5E is widely expressed, with the greatest expression detected in the heart, testis, and brain ( 159,177 ). INPP5E dephosphorylates at the 5-position PtdIns(3,4,5)P 3 ( 159,177,178 ), PtdIns(4,5)P 2 ( 159,178,179 ), and PtdIns(3,5)P 2 ( 177 ) in vitro. In contrast, other reports have suggested that neither PtdIns(4,5) P 2 ( 177 ) nor PtdIns(3,5)P 2 ( 178 ) are substrates for INPP5E in vitro.…”

Section: Phosphoinositide 4-phosphatase Activities and Cancermentioning

confidence: 99%

“…In keeping with these suggested disease consequences, INPP5E has been shown to regulate the levels of PtdIns(3,4,5)P 3 ( 184,185 ) and PtdIns(3,5)P 2 ( 184,185 ) in vivo. INPP5E overexpression inhibits AKT phosphorylation at Thr308 and Ser473 in response to PDGF ( 184 ) and insulin-like growth factor ( 178 ), demonstrating that INPP5E is a physiologically relevant negative regulator of PI3K/AKT signaling. Several studies have associated INPP5E with cancer; however, INPP5E expression has also been reported to be increased in some cancers, such as cervical ( 186 ), but in metastatic adenocarcinoma compared with primary tumors the expression of INPP5E is downregulated ( 187 ).…”

Section: Phosphoinositide 4-phosphatase Activities and Cancermentioning

confidence: 99%

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Phosphatidylinositolphosphate phosphatase activities and cancer

Rudge

Wakelam

2016

Journal of Lipid Research

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This article is available online at http://www.jlr.org kinase pathways in regulating phosphoinositide signaling; however, all signaling pathways are subject to negative as well as positive control, pointing to a key role for inositol phospholipid phosphatases in cell and tissue regulation in health and disease. This review focuses upon this aspect of regulation, considering the importance of the many phosphatases that can act upon phosphoinositides, and we further consider the importance of each in malignancy. PHOSPHOINOSITIDE 3-KINASESIn mammals, the phosphoinositide 3-kinase (PI3K) isoforms responsible for phosphorylating the 3-hydroxyl group of the inositol headgroup of PtdIns, PtdIns(4)P, and PtdIns(4,5)P 2 have been divided into three classes: class I, class II, and class III.In response to activation of cell surface receptors, class I PI3Ks are responsible for phosphorylating PtdIns(4,5)P 2 to generate PtdIns(3,4,5)P 3 ( 3 ). There are four class I PI3Ks that exist as heterodimers of regulatory and catalytic subunits. The four distinct catalytic subunits, p110 ␣ , -␤ , -␥ , and -␦ , are further divided into class IA (p110 ␣ , -␤ , and -␦ ) and class IB (p110 ␥ ). Class IA PI3Ks bind the SH2 domain containing the p85 family of regulatory subunits (p85 ␣ , p85 ␤ , and p55) that bind to protein tyrosine phosphate residues in activated receptors, thus relieving p85-mediated Abstract Signaling through the phosphoinositide 3-kinase pathways mediates the actions of a plethora of hormones, growth factors, cytokines, and neurotransmitters upon their target cells following receptor occupation. Overactivation of these pathways has been implicated in a number of pathologies, in particular a range of malignancies. The tight regulation of signaling pathways necessitates the involvement of both stimulatory and terminating enzymes; inappropriate activation of a pathway can thus result from activation or inhibition of the two signaling arms . The focus of this review is to discuss, in detail, the activities of the identifi ed families of phosphoinositide phosphatase expressed in humans, and how they regulate the levels of phosphoinositides implicated in promoting malignancy. A series of tightly regulated lipid kinase and phosphatase enzyme activities coordinately convert phosphatidylinositol (PtdIns) into a network of phosphorylated derivatives, collectively called phosphoinositides. These differ in the number and position of the phosphate groups on the inositol head group: three PtdIns monophosphate isomers [PtdIns(3)P, PtdIns(4)P, and PtdIns(5)P], three PtdIns bisphosphate isomers [PtdIns(3,4)P 2 , PtdIns(3,5) P 2 , and PtdIns(4,5)P 2 ], and a single trisphosphate isomer [PtdIns(3,4,5)Phosphoinositide signaling is an extensively studied topic with clear evidence linking the pathway from the kinase to activation of AKT and TOR to a number of disease states. While these include malignancies, there is also strong evidence for other diseases, such as overgrowth syndromes. Most studies have focused upon the importance of the ...

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“…82 Indeed, Inpp5E participates in growth factor signaling, primarily controlling hypothalamic responses to insulin stimulation. 82,84,98 It helps regulate basal levels of PI(3,4,5)P 3 in the hypothalamus, the main central nervous system (CNS) regulator of insulin signaling. 82 Inpp5E is abundantly expressed in the hypothalamus and is tyrosine phosphorylated by activated insulin receptor.…”

Section: Insulin Signaling and Glucose Homeostasismentioning

confidence: 99%

Role of Ocrl1 and Inpp5E in primary cilia assembly and maintenance: a phosphatidylinositol phosphatase relay system?

Madhivanan¹,

Ramadesika²,

Aguilar

2016

RRB

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Abstract:The primary cilium (PC) is a plasma membrane-derived structure of great importance for cell and organismal physiology. Indeed, abnormalities in assembly or function of the PC trigger the onset of a group of genetic diseases collectively known as ciliopathies. In recent years, it has become evident that the integrity and function of the PC depends substantially on signaling elements such as phosphoinositides (PI) and their regulators. Because phospholipids such as PI(4,5)P 2 constitute recruitment platforms for cytoskeleton, signaling, and trafficking machinery, control over their levels is critical for PC function. Although information about phosphoinositol phosphate (PIP) kinases in the PC is scarce, a growing body of evidence supports a role for PIP phosphatases in cilia assembly/maintenance. Indeed, deficiencies in two 5′ PIP phosphatases, Inpp5E and Ocrl1, are clearly linked to ciliopathies like Joubert/MORM syndromes, or ciliopathy-associated dise ases like Lowe syndrome. Here, we review the unique roles of these proteins and their specific site of action for ensuring ciliary integrity. Further, we discuss the possibility that a phosphatase relay system able to pass PI control from a preciliary to an intraciliary compartment is in place to ensure PC integrity/function.

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Regulation of IGF-1/PI3K/Akt signalling by the phosphoinositide phosphatase pharbin

Cited by 15 publications

References 36 publications

INPP5E Preserves Genomic Stability through Regulation of Mitosis

INPP5E Preserves Genomic Stability through Regulation of Mitosis

Phosphatidylinositolphosphate phosphatase activities and cancer

Role of Ocrl1 and Inpp5E in primary cilia assembly and maintenance: a phosphatidylinositol phosphatase relay system?

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