Identification of a Novel Domain in Two Mammalian Inositol-polyphosphate 5-Phosphatases That Mediates Membrane Ruffle Localization

Gurung, Rajendra; Tan, April; Ooms, Lisa M; Mcgrath, Meagan Jane; Huysmans, Richard D; Munday, Adam D.; Prescott, Mark; Whisstock, James C.; Mitchell, Christina A.

doi:10.1074/jbc.m209991200

Cited by 87 publications

(53 citation statements)

References 51 publications

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“…This C-terminal domain is adjacent to the PtdIns(3,4,5)P 3 5-phosphatase domain of PIPP. The SKICH/ PRD domain has been shown previously to facilitate phosphatase access to both the plasma membrane and also the neurite growth cone (16,29). Notably, we demonstrate here the PIPP growth cone localization is CRMP2 dependent, as revealed by decreased PIPP staining in the growth cones of CRMP2 knockdown cells.…”

Section: Discussionsupporting

confidence: 71%

“…1A). PIPP localizes to the growth cone of NGF-stimulated PC12 cells, and is targeted to this site by its C-terminal SKICH domain (16,29). We investigated if PIPP complexes with other proteins that regulate neurite outgrowth or differentiation by undertaking a Y2H screen of a human fetal brain library using the C-terminal proline-rich domain (727-1003 amino acids) of PIPP as bait (PIPP SKICH/PRD-2 ).…”

Section: Y2h Screening Identifies ␤Ii Tubulin and Crmp1 As Pippbindinmentioning

confidence: 99%

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Identification of a Proline-rich Inositol Polyphosphate 5-Phosphatase (PIPP)·Collapsin Response Mediator Protein 2 (CRMP2) Complex That Regulates Neurite Elongation

Astle

Ooms

Cole

et al. 2011

Journal of Biological Chemistry

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Neuron polarization is essential for the formation of one axon and multiple dendrites, establishing the neuronal circuitry. Phosphoinositide 3-kinase (PI3K) signaling promotes axon selection and elongation. Here we report in hippocampal neurons siRNA knockdown of the proline-rich inositol polyphosphate 5-phosphatase (PIPP), which degrades PI3K-generated PtdIns(3,4,5)P 3 , results in multiple hyperelongated axons consistent with a polarization defect. We identify collapsin response mediator protein 2 (CRMP2), which regulates axon selection by promoting WAVE1 delivery via Kinesin-1 motors to the axon growth cone, as a PIPP-interacting protein by Y2H screening, direct binding studies, and coimmunoprecipitation of an endogenous PIPP, CRMP2, and Kinesin-1 complex from brain lysates. The C-terminal growth cone-targeting domain of PIPP facilitates its interaction with CRMP2. PIPP growth cone localization is CRMP2-dependent. PIPP knockdown in PC12 cells promotes neurite elongation, WAVE1 and Kinesin-1 growth cone localization, whereas knockdown of CRMP2 exhibits the opposite phenotype, with shorter neurites and decreased WAVE1/Kinesin-1 at the growth cone. In contrast, CRMP2 overexpression promotes neurite elongation, a phenotype rescued by full-length PIPP, or expression of the CRMP2-binding PIPP domain. Therefore this study identifies PIPP and CRMP2 exert opposing roles in promoting axon selection and neurite elongation and the complex between these proteins serves to regulate the localization of effectors that promote neurite extension.Neurons are highly polarized cells that contain one long axon, which transmits information, and multiple shorter dendrites, which receive information (1, 2). The formation of axon/ dendrite polarity is critical for normal brain function. Neurons form networks connecting via synapses to other neurons, by extending axons in a process of neurite outgrowth and elongation. An actin-rich area at the tip of extending neurites, called the growth cone, enables neurite extension. Many signaling and actin regulatory factors function at the growth cone to promote neurite outgrowth and extension (2).The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway promotes both neuronal polarity and neurite extension. In response to nerve growth factor (NGF) stimulation PI3K phosphorylates PtdIns(4,5)P 2 3 to form PtdIns(3,4,5)P 3 , a lipid signal that promotes neurite differentiation (3). In elongating neurons PtdIns(3,4,5)P 3 activates Rho GTPases Cdc42 and Rac1 that in turn regulate growth cone actin dynamics facilitating growth cone advancement (4, 5). PtdIns(3,4,5)P 3 also binds and activates the serine/threonine kinase Akt, which phosphorylates numerous targets, including Tau, GSK3␤, Ezrin, and Pak1 to regulate neuronal polarity, neurite outgrowth, and elongation (6, 7). GSK3␤ is inactivated by Akt phosphorylation (8) in the nascent growth cone (7, 9, 10). GSK3␤ effectors include CRMP2 (11, 12) and adenomatous polyposis coli (10, 13), which promote microtubule polymerization in the nascent axon driv...

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Section: Discussionsupporting

confidence: 71%

Section: Y2h Screening Identifies ␤Ii Tubulin and Crmp1 As Pippbindinmentioning

confidence: 99%

Identification of a Proline-rich Inositol Polyphosphate 5-Phosphatase (PIPP)·Collapsin Response Mediator Protein 2 (CRMP2) Complex That Regulates Neurite Elongation

Astle

Ooms

Cole

et al. 2011

Journal of Biological Chemistry

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“…n type 2 diabetes mellitus, insulin resistance is characterized by an impairment of glucose uptake in skeletal muscle (1)(2)(3). Skeletal muscle insulin resistance is considered to be an initial metabolic defect in the development of this disease (4,5).…”

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confidence: 99%

Phosphatidylinositol 3,4,5-Trisphosphate Phosphatase SKIP Links Endoplasmic Reticulum Stress in Skeletal Muscle to Insulin Resistance

Ijuin

Hosooka

Takenawa

2016

Molecular and Cellular Biology

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cInsulin resistance is critical in the pathogenesis of type 2 diabetes. Endoplasmic reticulum (ER) stress in liver and adipose tissues plays an important role in the development of insulin resistance. Although skeletal muscle is a primary site for insulin-dependent glucose disposal, it is unclear if ER stress in those tissues contributes to insulin resistance. In this study, we show that skeletal muscle kidney-enriched inositol polyphosphate phosphatase (SKIP), a PIP 3 (phosphatidylinositol-3,4,5-trisphosphate) phosphatase, links ER stress to insulin resistance in skeletal muscle. SKIP expression was increased due to ER stress and was higher in the skeletal muscle isolated from high-fat-diet-fed mice and db/db mice than in that from wild-type mice. Mechanistically, ER stress promotes activating transcription factor 6 (ATF6) and X-box binding protein 1 (XBP1)-dependent expression of SKIP. These findings underscore the specific and prominent role of SKIP in the development of insulin resistance in skeletal muscle.

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“…In N1E-115 neuroblastoma cells, human Inpp5k regulates the actin cytoskeleton [19]. Human Inpp5k is translocated from the endoplasmic reticulum to plasma membrane ruffles following activation by EGF and insulin in Cos-7 and skeletal muscle C2C12 cell lines, respectively [16,39]. Activation of PKB and p70 S6 kinases as well as GLUT4 glucose transporter translocation to the plasma membrane and membrane ruffles formation were significantly decreased in human Inpp5k-transfected and insulinstimulated CHO cells [20].…”

Section: The Inositol Inpp5k 5-phosphatase Affects Osmoregulation Thrmentioning

confidence: 99%

The inositol Inpp5k 5-phosphatase affects osmoregulation through the vasopressin-aquaporin 2 pathway in the collecting system

Pernot

Terryn

Cheong

et al. 2011

Pflugers Arch - Eur J Physiol

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Inositol Inpp5k (or Pps, SKIP) is a member of the inositol polyphosphate 5-phosphatases family with a poorly characterized function in vivo. In this study, we explored the function of this inositol 5-phosphatase in mice and cells overexpressing the 42-kDa mouse Inpp5k protein. Inpp5k transgenic mice present defects in water metabolism characterized by a reduced plasma osmolality at baseline, a delayed urinary water excretion following a water load, and an increased acute response to vasopressin. These defects are associated with the expression of the Inpp5k transgene in renal collecting ducts and with alterations in the arginine vasopressin/aquaporin-2 signalling pathway in this tubular segment. Analysis in a mouse collecting duct mCCD cell line revealed that Inpp5k overexpression leads to increased expression of the arginine vasopressin receptor type 2 and increased cAMP response to arginine vasopressin, providing a basis for increased aquaporin-2 expression and plasma membrane localization with increased osmotically induced water transport. Altogether, our results indicate that Inpp5k 5-phosphatase is important for the control of the arginine vasopressin/aquaporin-2 signalling pathway and water transport in kidney collecting ducts. [13,17, 29, 40]. It also regulates the activity of many ion channels and transporters [35,36]. PtdIns(4,5)P2 is mainly localized in the inner leaflet of plasma membranes, but smaller pools have been detected in intracellular membranes, including Golgi, endoplasmic reticulum, endosomes and lamellipodia [13]. Mechanistically, a very large number of proteins are recruited to PtdIns(4,5)P2 via pleckstrin homology (PH), phagocyte oxidase (PX), Fab1p, YOTB, Vac1p and EEA1 (FYVE), epsin N-terminal homology (ENTH) domains or through small patches of basic amino acids [13,18, 28]. PtdIns(4,5,)P2 also serves as precursor of five essential signalling molecules: diacylglycerol, inositol (1,4,5)-trisphosphate, PtdIns4P, PtdIns5P and PtdIns(3,4,5)P3 [13,17]. In non stimulated cells, PtdIns(3,4,5)P3 levels are very low in the plasma membrane, reaching ~0.1% of the level of PtdIns(4,5)P2 [13,17]. Upon cell activation, PtdIns(3,4,5)P3 levels are transiently increased by a factor ranging from 2-to 100-fold. This phosphoinositide is implicated in the control of cell survival, growth and proliferation, resistance to apoptosis, regulation of cytoskeleton dynamics, membrane trafficking, cell migration, and many of the metabolic responses to insulin [12,13].PtdIns(3,4,5)P3 regulates a wide variety of effector proteins primarily by binding and recruiting specific proteins.In mammalian cells, PtdIns(4,5)P2 and/or PtdIns(3,4,5)P3 are substrates for several members of the phosphoinositide 5-phosphatases family, including Inppl1 (or

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Identification of a Novel Domain in Two Mammalian Inositol-polyphosphate 5-Phosphatases That Mediates Membrane Ruffle Localization

Cited by 87 publications

References 51 publications

Identification of a Proline-rich Inositol Polyphosphate 5-Phosphatase (PIPP)·Collapsin Response Mediator Protein 2 (CRMP2) Complex That Regulates Neurite Elongation

Identification of a Proline-rich Inositol Polyphosphate 5-Phosphatase (PIPP)·Collapsin Response Mediator Protein 2 (CRMP2) Complex That Regulates Neurite Elongation

Phosphatidylinositol 3,4,5-Trisphosphate Phosphatase SKIP Links Endoplasmic Reticulum Stress in Skeletal Muscle to Insulin Resistance

The inositol Inpp5k 5-phosphatase affects osmoregulation through the vasopressin-aquaporin 2 pathway in the collecting system

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