PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K

Malek, Mouhannad; Kielkowska, Anna; Chessa, Tamara; Anderson, Karen E.; Barneda, David; Pir, Pınar; Nakanishi, Hiroki; Eguchi, Satoshi; Koizumi, Atsushi; Sasaki, Junko; Juvin, Veronique; Kiselev, Vladimir Yu; Niewczas, Izabella; Gray, Alexander; Valayer, Alexandre; Spensberger, Dominik; Imbert, Marine; Felisbino, Sérgio Luís; Habuchi, Tomonori; Beinke, Sören; Cosulich, Sabina C.; Novère, Nicolas Le; Sasaki, Takehiko; Clark, Jonathan; Hawkins, Phillip T.; Stephens, Len R.

doi:10.1016/j.molcel.2017.09.024

Cited by 146 publications

(164 citation statements)

References 69 publications

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“…We then demonstrate that the class I PI3K pathway, acting via PIP3 synthesis, dominates PI(3,4)P2 accumulation in cells. Our data also support the recently proposed direct degradation of both PI(3,4)P2 and PIP3 by the lipid phosphatase and tumor suppressor PTEN (Malek et al, 2017). Collectively, our data show that the class I PI3K pathway is the most potent driver of PI(3,4)P2-dependent signaling.…”

Section: Introductionsupporting

confidence: 90%

A High Avidity Biosensor Reveals PI(3,4)P₂ is Predominantly a Class I PI3K Signaling Product

Pacheco

Dull

et al. 2018

Preprint

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Class I PI 3-kinase (PI3K) signaling is central to animal growth and metabolism, and disruption of this pathway occurs frequently in cancer and diabetes. However, the specific spatial/temporal dynamics and signaling roles of its minor lipid messenger, phosphatidylinositol (3,4)bisphosphate [PI(3,4)P2], are not well understood. This owes principally to a lack of tools to study this scarce lipid. Here, we developed a high sensitivity genetically encoded biosensor for PI(3,4)P2, demonstrating high selectivity and specificity of the sensor for the lipid. We show that despite clear evidence for class II PI3K in PI(3,4)P2-driven function, the overwhelming majority of the lipid accumulates through degradation of class I PI3K-produced PIP3. However, we show that PI(3,4)P2 is also subject to hydrolysis by the tumor suppressor lipid phosphatase PTEN.Collectively, our results show that PI(3,4)P2 is potentially an important driver of class I PI3Kdriven signaling, and provides powerful new tools to begin to resolve the biological functions of this lipid downstream of class I and II PI3K.

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Section: Introductionsupporting

confidence: 90%

A High Avidity Biosensor Reveals PI(3,4)P₂ is Predominantly a Class I PI3K Signaling Product

Pacheco

Dull

et al. 2018

Preprint

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“…INPP4B is known to dephosphorylate phosphatidylinositol 3,4-bisphosphate in the PI3K pathway, which co-activates cell growth and movement via Akt kinases (Malek et al, 2017).…”

Section: Biological Relevance Of the Key Proteins Selected By The Decmentioning

confidence: 99%

Breast cancer classification based on proteotypes obtained by SWATH mass spectrometry

Bouchal

Schubert

Faktor

et al. 2019

Preprint

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Accurate breast cancer classification is vital for patient management decisions, and better tumour classification is expected to enable more precise and eventually personalized treatment to improve patient outcomes. Here, we present a novel quantitative proteotyping approach based on SWATH mass spectrometry and establish key proteins for breast tumour classification derived from proteotype data. The study was based on 96 tissue samples representing five breast cancer subtypes according to conventional classification. Correlation of SWATH proteotype patterns indicated groups that largely recapitulate these subtypes. However, 2 the proteotype-based classification also revealed varying degrees of heterogeneity within the conventional subtypes, with triple negative tumours being the most heterogeneous. Proteins that contributed most strongly to the proteotype-based classification include INPP4B, CDK1, and ERBB2, which are associated with oestrogen receptor status, tumour grade, and HER2 status, respectively. While these three key proteins exhibited high levels of correlation between protein and transcript levels (R>0.67), general correlation did not exceed R=0.29, indicating the value of protein-level measurements of biomarkers and disease-regulated genes. Overall, our data shows how large-scale protein-level measurements by next-generation proteomics can lead to improved patient stratification for precision medicine.

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“…One difficulty in understanding its mechanism is that in addition to functioning as a lipid phosphatase (PTEN opposes PI3K by converting PIP3 back to PIP2) it also has protein phosphatase activity (Kreis et al, 2014). It is now also apparent that PTEN not only dephosphorylates PI(3,4,5)P3, but also functions as a PI(3,4)P2 phosphatase, a role linked with cancer invasion (Malek et al, 2017). Our findings argue in favour of PTEN functioning through the regulation of PIP3, and confirm the importance of this molecule in the regulation of axon regeneration.…”

Section: Discussionmentioning

confidence: 99%

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS

Barber

Evans

Nieuwenhuis

et al. 2019

Preprint

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Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol(3,4,5)-trisphosphate (PIP3). We found that neuronal PIP3 decreases with maturity in line with regenerative competence, firstly in the cell body and subsequently in the axon. We show that adult PNS neurons utilise two catalytic subunits of PI3K for efficient regeneration: p110α and p110δ. Overexpressing p110α in CNS neurons had no effect, however expression of p110δ restored axonal PIP3 and enhanced CNS regeneration in rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings demonstrate a deficit of axonal PIP3 as a reason for intrinsic regeneration failure and show that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion. KeywordsAxon, axon regeneration, CNS regeneration, optic nerve, neuronal signalling, phosphoinositide 3-kinase, PI3K, p110 delta, phosphatidylinositol(3,4,5)-trisphosphate, PIP3.

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PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K

Cited by 146 publications

References 69 publications

A High Avidity Biosensor Reveals PI(3,4)P₂ is Predominantly a Class I PI3K Signaling Product

A High Avidity Biosensor Reveals PI(3,4)P₂ is Predominantly a Class I PI3K Signaling Product

Breast cancer classification based on proteotypes obtained by SWATH mass spectrometry

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS

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PTEN Regulates PI(3,4)P2 Signaling Downstream of Class I PI3K

Cited by 146 publications

References 69 publications

A High Avidity Biosensor Reveals PI(3,4)P2 is Predominantly a Class I PI3K Signaling Product

A High Avidity Biosensor Reveals PI(3,4)P2 is Predominantly a Class I PI3K Signaling Product

Breast cancer classification based on proteotypes obtained by SWATH mass spectrometry

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS

Contact Info

Product

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A High Avidity Biosensor Reveals PI(3,4)P₂ is Predominantly a Class I PI3K Signaling Product

A High Avidity Biosensor Reveals PI(3,4)P₂ is Predominantly a Class I PI3K Signaling Product