Myotubularin-related Protein 4 (MTMR4) Attenuates BMP/Dpp Signaling by Dephosphorylation of Smad Proteins

Yu, Junjing; He, Xiaomeng; Chen, Ye-Guang; Yan, Huimin; Yang, Shuo; Wang, Lei; Pan, Lei; Tang, Hong

doi:10.1074/jbc.m112.413856

Cited by 21 publications

(25 citation statements)

References 42 publications

(41 reference statements)

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“…Conversely, dephosphorylation of Smad1/5/8 represents a critical event in terminating BMP signaling. Phosphatases that have been reported to dephosphorylate Smad1/5/8 include the panSmad phosphatase PPM1A (19,20), SCP1/2/3 (22, 24), PDPs (21), and MTMR4 (23). In various cell types, we found that PPM1A, but not the others, plays a major role of pan-Smad dephosphorylation (19).…”

Section: Depletion Of Ppm1a Does Not Fully Sustain Smad1mentioning

confidence: 67%

“…Several phosphatases were identified as the phosphatases toward the dephosphorylation of R-Smads, including PPM1A as a pan-Smad phosphatase (19,20). Smad1 is also reported to be dephosphorylated by pyruvate dehydrogenase phosphatase (PDP) (21), small C-terminal phosphatases (SCP1/2/3) (22), and endosomal phosphatase MTMR4 (23). Meanwhile, SCP1/2/3 can target the linker region of R-Smads (22,24,25) In this study, we showed that knockdown of PPM1A failed to completely restore the level of phospho-Smad1 (P-Smad1), suggesting the existence of other phosphatases toward P-Smad1.…”

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confidence: 99%

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C-terminal Domain (CTD) Small Phosphatase-like 2 Modulates the Canonical Bone Morphogenetic Protein (BMP) Signaling and Mesenchymal Differentiation via Smad Dephosphorylation

Zhao

Xiao

Sun

et al. 2014

Journal of Biological Chemistry

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Background: Dephosphorylation of R-Smads in the nucleus shuts off TGF-␤ superfamily signaling. Results: SCP4 specifically dephosphorylates BMP-activated Smad1/5/8, but not TGF-␤-activated Smad2/3, and ectopic expression of SCP4 inhibits BMP signaling, whereas SCP4 depletion enhances BMP signaling. Conclusion: SCP4 is a nuclear phosphatase terminating BMP signaling. Significance: Identification of SCP4 may suggest its physiological functions in BMP-induced cellular processes and relevant diseases.

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Section: Depletion Of Ppm1a Does Not Fully Sustain Smad1mentioning

confidence: 67%

mentioning

confidence: 99%

C-terminal Domain (CTD) Small Phosphatase-like 2 Modulates the Canonical Bone Morphogenetic Protein (BMP) Signaling and Mesenchymal Differentiation via Smad Dephosphorylation

Zhao

Xiao

Sun

et al. 2014

Journal of Biological Chemistry

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“…Also, MTMR4 colocalizes with the exocyst subunit Sec15 and affects localization of VAMP3-containing endosomes (Lorenzo, Urbe et al 2006;Naughtin, Sheffield et al 2010). Additionally to PI(3)P, MTMR4 dephosphorylates RSmads at early endosomes and thereby negatively regulates TGF-β (transforming growth factor) (Yu, Pan et al 2010) and BMP (bone morphogenetic protein) signaling pathways (Yu, He et al 2013). …”

Section: Other Myotubularin Family Members Contribute To Endosomal Pimentioning

confidence: 99%

A phosphoinositide conversion mechanism for exit from endosomes

Ketel¹,

Krauß²,

Nicot³

et al. 2016

Nature

157

177

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I owe special thanks to Marnix Wieffer and Michael Krauß, who spent a lot of time helping me to get started in the lab, to overcome numerous experimental problem, I was not sure how to deal with, and frequently joined in discussions about my project with excellent advice. I am really grateful for your experimental support, Michael, and the time you invested in the project during our paper revision.Further, I would like to thank Jocelyn Laporte and his group, especially Anne-Sophie Nicot, at the IGBMC in Strasbourg for their support and a very fruitful collaboration, and Carsten Schultz and his group at the EMBL in Heidelberg for their support and constant supply with PIP/AMs. I owe special thanks to Dmytro Puchkov for the ultrastructural analysis and Eberhard Krause for mass spectrometry done within this project. I also need to acknowledge Markus Wenk and Federico Torta at the Singapore Lipidomics Incubator for joining the project at a very late stage, when we urgently needed help from lipidomics specialists. It was a pity that experiments did not work out as planned.I would further like to express my gratitude to two very skilled technicians in the AG Haucke lab: Silke Zillmann and Delia Löwe. Without your help it would have been impossible to achieve so much within the limited amount of time I had during the paper revision. by VPS34-IN1 treatment................................................... 52 2.3.11 Fluorescence microscopy................................................................................. 53 2.3.12 Flow cytometry............................................................................................ III SummaryPhosphoinositides (PIs) are a minor class of short-lived phospholipids that serve as crucial signposts of membrane identity. Thereby, PIs full fill important functions in cell signaling and membrane transport. PI 4-phosphates such as phosphatitylinositol-4-phosphate (PI(4)P) and phosphatitylinositol-4,5-bisphosphate (PI(4,5)P 2 ) are enriched at the plasma membrane (PM), on secretory organelles and lysosomes, while PI 3-phosphates, i.e.phosphatitylinositol-3-phosphate (PI(3)P), are a hallmark of the endosomal system.Directional transport between these compartments, thus, requires regulated PI conversion.However, PI conversion in exit from PI(3)P-enriched endosomes en route to the PI(4)P-and PI(4,5)P 2 -positive PM in endosomal recycling remained unknown.Here, we report that cargo exit from endosomes requires removal of PI(3)P by the PI(3)P 3-phosphatase myotubularin 1 (MTM1), and concomitant PI(4)P synthesis by PI 4-kinase type II α (PI4K2α). Loss of MTM1 causes endosomal accumulation of PI(3)P and PI(3)P effector proteins, i.e. sorting nexins, Kif16b-mediated outward traffic of PI(3)P containing endosomes and sub-plasmalemmal accumulation of exocytosis-deficient endosomes. As PI4K2α associates with MTM1 and thereby facilitates membrane recruitment of MTM1, these phenotypic changes are mimicked by loss of PI4K2α. The conversion of PI(3)P-to-PI(4)P is paralleled by a switch i...

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“…15 Pyruvate dehydrogenase phosphatase (PDP), which is localized in mitochondria, was the first phosphatase to be reported as a SMAD1 tail phosphatase. 16 In addition, SCPs were proposed to be a SMAD1 tail phosphatase through depletion and overexpression studies.…”

Section: +mentioning

confidence: 99%

Selective Dephosphorylation by SCP1 and PP2A in Phosphorylated Residues of SMAD2

Hong¹,

Sung²,

Lee³

et al. 2014

Bulletin of the Korean Chemical Society

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Protein phosphatase is important for cellular events, and a family of protein phosphatases, the so-called C-terminal domain (CTD) of RNA polymerase II (RNAPII) phosphatases, has recently attracted attention. The CTD is the largest subunit of RNAPII and consists of a tandem repeated heptapeptide (Y 1 S 2 P 3 T 4 S 5 P 6 S 7 ).1 Seven active CTD phosphatases in the human genome are known and share the same catalytic domain architecture and DXDX(T/V) active site motif.2 Small CTD phosphatase 1 (SCP1) dephosphorylates the fifth phosphorylated serine of Y 1 S 2 P 3 T 4 S 5 P 6 S 7 in the CTD 2 and has been renamed CTD small phosphatase 1 (CTDSP1). Small CTD phosphatase 2 (SCP2) and small CTD phosphatase 3 (SCP3) have a similar sequence, threedimensional structure, and biochemical function to SCP1.

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Myotubularin-related Protein 4 (MTMR4) Attenuates BMP/Dpp Signaling by Dephosphorylation of Smad Proteins

Cited by 21 publications

References 42 publications

C-terminal Domain (CTD) Small Phosphatase-like 2 Modulates the Canonical Bone Morphogenetic Protein (BMP) Signaling and Mesenchymal Differentiation via Smad Dephosphorylation

C-terminal Domain (CTD) Small Phosphatase-like 2 Modulates the Canonical Bone Morphogenetic Protein (BMP) Signaling and Mesenchymal Differentiation via Smad Dephosphorylation

A phosphoinositide conversion mechanism for exit from endosomes

Selective Dephosphorylation by SCP1 and PP2A in Phosphorylated Residues of SMAD2

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