The inositol 5-phosphatase INPP5K participates in the fine control of ER organization

Dong, Rui; Zhu, Tingshun; Benedetti, Lorena; Gowrishankar, Swetha; Deng, Huichao; Cai, Yiying; Wang, Xiangming; Shen, Kang; Camilli, Pietro De

doi:10.1083/jcb.201802125

Cited by 42 publications

(81 citation statements)

References 42 publications

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“…Those rare mutations also impair catalytic activity. Moreover, in the case of the worm orthologue of INPP5K, the same mutations could also affect the fine control of the endoplasmic reticulum network organization (69). Thus, genetic evidence of very specific human diseases argues against the redundancy between PI 5-phosphatases and suggests that in a genetic context PI 5-phosphatase could have very specific and individual functions.…”

Section: Pi 5-phosphatase Mutations Argue In Favor Of Specificity Of mentioning

confidence: 99%

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

Ramos

Ghosh

Erneux

2019

Journal of Lipid Research

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Phosphoinositides (PIs) are recognized as major signaling molecules in many different functions of eukaryotic cells. PIs can be dephosphorylated by multiple phosphatase activities at the 5-, 4- and 3- positions. Human PI 5-phosphatases belong to a family of 10 members. Except for INPP5A, they all catalyze the dephosphorylation of PI(4,5)P2 and/or PI(3,4,5)P3 at the 5- position. PI 5-phosphatases thus directly control the levels of PI(3,4,5)P3 and also participate in fine-tuning regulatory mechanisms of PI(3,4)P2 and PI(4,5)P2. Second messenger functions have been demonstrated for PI(3,4)P2 in invadopodium maturation and in lamellipodia formation. PI 5-phosphatases can use several substrates on isolated enzymes, and it has been challenging to establish their real substrate in vivo. PI(4,5)P2 has multiple functions in signaling, including interaction with scaffold proteins, ion channels, and cytoskeleton proteins. PI 5-phosphatase isoenzymes have been individually implicated in human diseases, such as the oculocerebrorenal syndrome of Lowe, through mechanisms which include lipid-controlling. Oncogenic and tumor suppressive functions of PI 5-phosphatases have also been reported in different cell contexts. The mechanisms responsible for genetic diseases and for tumor suppressor or oncogenic functions are not fully understood. The regulation of PI 5-phosphatases is thus crucial in understanding cell functions.

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Section: Pi 5-phosphatase Mutations Argue In Favor Of Specificity Of mentioning

confidence: 99%

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

Ramos

Ghosh

Erneux

2019

Journal of Lipid Research

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“…In U‐251 MG cells platted on FN, we have shown the colocalization between SKIP and SHIP2 in ruffles as well as with PI(4,5)P2. In other reports, there is controversy about PI(4,5)P2 measurements in SKIP‐depleted cells: in siRNA for SKIP‐transfected cells, PI(4,5)P2 was upregulated in U‐87 MG cells but unchanged in HeLa cells . This prompted us to check for PI(4,5)P2 content at the plasma membrane in three GBM cell lines upon adhesion on FN.…”

Section: Discussionmentioning

confidence: 94%

“…Both SKIP and SHIP2 have been reported to influence cell migration in GBM but it is not clear whether the two phosphatases work together in this mechanism or even if they use a common lipid substrate such as PI(4,5)P2 [5,10]. Moreover, SKIP has been reported to localize at the surface of the endoplasmic reticulum (ER) which is unique among the various PI 5-phosphatases [11,12]. This location is surprising for a PI 5-phosphatase given the absence of PI(4,5)P2 and PI (3,4,5)P3 in the ER.…”

Section: Introductionmentioning

confidence: 99%

Lipid phosphatases SKIP and SHIP2 regulate fibronectin‐dependent cell migration in glioblastoma

et al. 2019

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Cell migration is an important process that occurs during development and has also been linked to the motility of cancer cells. Cytoskeleton reorganization takes place in the migration process leading to lamellipodia formation. Understanding the molecular underpinnings of cell migration is particularly important in studies of glioblastoma, a highly invasive and aggressive cancer type. Two members of the phosphoinositide 5‐phosphatase family, SKIP and SHIP2, have been associated with cell migration in glioblastoma; however, the precise role these enzymes play in the process—and whether they work in concert—remains unclear. Here, we compared phosphoinositide 5‐phosphatases expression in glioblastoma primary cells and cell lines and showed that SHIP2 and SKIP expression greatly varies between different cell types, while OCRL, another phosphoinositide 5‐phosphatase, is constitutively expressed. Upon adhesion of U‐251 MG cells to fibronectin, SHIP2, SKIP, and PI(4,5)P2 colocalized in membrane ruffles. Upregulation of PI(4,5)P2 was observed in SKIP‐depleted U‐251 MG cells compared to control cells, but only when cells were adhered to fibronectin. Both PTEN‐deficient (U‐251) and PTEN‐containing (LN229) glioblastoma cells showed a decrease in cell migration velocity in response to SKIP downregulation. Moreover, a SHIP2 catalytic inhibitor lowered cell migration velocity in the U‐251 MG cell line. We conclude that integrin activation in U‐251 cells leads to colocalization of both SKIP and SHIP2 in ruffles, where they act as potential drivers of cell migration. Depending on their expression levels in glioblastoma, phosphoinositide 5‐phosphatases could cooperate and synergize in the regulation of cell migration and adhesion.

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“…Presumably, these domains bind other proteins and might diversify the function of the Rtns and REEPs. In addition, several Rtn-like proteins have been discovered, including Tts1 in S. pombe (Zhang and Oliferenko, 2014;Zhang et al, 2010) and its homologs in other organisms, the ER autophagy receptor FAM134 (also known as RETREG1) (Khaminets et al, 2015) and ARL6IP1, which recruits an inositol 5-phosphatase to the ER (Dong et al, 2018). Whether these proteins induce high membrane curvature and whether such an effect is required for their functions remains to be investigated.…”

Section: Future Perspectivesmentioning

confidence: 99%

Reconstituting the reticular ER network – mechanistic implications and open questions

Wang

Rapoport

2019

Journal of Cell Science

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The endoplasmic reticulum (ER) is a major membrane-bound organelle in all eukaryotic cells. This organelle comprises morphologically distinct domains, including the nuclear envelope and peripheral sheets and tubules. The tubules are connected by three-way junctions into a network. Several membrane proteins have been implicated in network formation; curvature-stabilizing proteins generate the tubules themselves, and membrane-anchored GTPases fuse tubules into a network. Recent experiments have shown that a tubular network can be formed with reconstituted proteoliposomes containing the yeast membrane-fusing GTPase Sey1 and a curvature-stabilizing protein of either the reticulon or REEP protein families. The network forms in the presence of GTP and is rapidly disassembled when GTP hydrolysis of Sey1 is inhibited, indicating that continuous membrane fusion is required for its maintenance. Atlastin, the ortholog of Sey1 in metazoans, forms a network on its own, serving both as a fusion and curvature-stabilizing protein. These results show that the reticular ER can be generated by a surprisingly small set of proteins, and represents an energydependent steady state between formation and disassembly. Models for the molecular mechanism by which curvature-stabilizing proteins cooperate with fusion GTPases to form a reticular network have been proposed, but many aspects remain speculative, including the function of additional proteins, such as the lunapark protein, and the mechanism by which the ER interacts with the cytoskeleton. How the nuclear envelope and peripheral ER sheets are formed remain major unresolved questions in the field. Here, we review reconstitution experiments with purified curvature-stabilizing proteins and fusion GTPases, discuss mechanistic implications and point out open questions.

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The inositol 5-phosphatase INPP5K participates in the fine control of ER organization

Cited by 42 publications

References 42 publications

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

Lipid phosphatases SKIP and SHIP2 regulate fibronectin‐dependent cell migration in glioblastoma

Reconstituting the reticular ER network – mechanistic implications and open questions

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