Active Transport of the Ubiquitin Ligase MID1 along the Microtubules Is Regulated by Protein Phosphatase 2A

Aranda-Orgillés, Beatriz; Aigner, J.; Kunath, Melanie; Lurz, Rudi; Schneider, Rainer; Schweiger, Susann

doi:10.1371/journal.pone.0003507

Cited by 39 publications

(42 citation statements)

References 36 publications

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“…␣4 functions as a novel regulatory subunit of protein phosphatase 2A (PP2A), 2 PP4, and PP6 (6 -10). With respect to PP2A, ␣4 binds the catalytic subunit (PP2Ac), at which time it is thought to displace the scaffolding (PP2Aa, PR65) and regulatory subunits (PP2Ab) that typically constitute the PP2A heterotrimeric complex (6,(11)(12)(13). Under growthpromoting conditions, ␣4 down-regulates PP2A activity within the mTOR signaling pathway, resulting in the downstream activation of eIF-4E and S6 kinase and the initiation of cell cycle progression (4,14,15).…”

Section: Alpha4 (␣4) Is a Key Regulator Of Protein Phosphatase 2a (Ppmentioning

confidence: 99%

“…Given the promiscuity of PP2A, the MID1-␣4-PP2Ac complex likely participates in the regulation of many different cellular processes. For example, this complex has been shown to directly regulate mTORC1 signaling as well as associate with the translational apparatus to regulate translation of various mRNAs including those for MID1 itself (6,8,10,16,26). In each case, it has been concluded that this regulatory role is conferred by MID1-mediated ubiquitination of PP2Ac (6,8,10,28).…”

Section: Alpha4 (␣4) Is a Key Regulator Of Protein Phosphatase 2a (Ppmentioning

confidence: 99%

“…MID1 Facilitates Polyubiquitination of ␣4 in Vitro-We recently characterized the interaction between the MID1 Bbox1 domain and ␣4 (6, 8, 21) using a 45-amino acid peptide derived from the C-terminal region of ␣4 (␣4 45 , residues 236 -280) that was shown to bind strongly to MID1 (6). We observed that ␣4 45 interacted with the Bbox1 domain at a site that was close to Lys-153, the lysine that is autoubiquitinated (19,21).…”

Section: Mid1 Facilitates In Vivo Proteasomalmentioning

confidence: 99%

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The MID1 E3 Ligase Catalyzes the Polyubiquitination of Alpha4 (α4), a Regulatory Subunit of Protein Phosphatase 2A (PP2A)

Huang²,

Zaghlula

et al. 2013

Journal of Biological Chemistry

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Background: IGBP1/␣4 interacts with microtubule-associated MID1 to regulate PP2A within the mTOR pathway. Results: MID1 catalyzes the polyubiquitination and degradation of ␣4, demonstrating for the first time a mechanism for ␣4 regulation. Conclusion:The tandem RING-Bbox domains are required for ␣4 polyubiquitination and degradation. Significance: Ectopic overexpression of IGBP1/␣4 transforms cells. Ubiquitination of ␣4 impacts the stability and activity level of PP2A.

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Section: Alpha4 (␣4) Is a Key Regulator Of Protein Phosphatase 2a (Ppmentioning

confidence: 99%

Section: Alpha4 (␣4) Is a Key Regulator Of Protein Phosphatase 2a (Ppmentioning

confidence: 99%

Section: Mid1 Facilitates In Vivo Proteasomalmentioning

confidence: 99%

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The MID1 E3 Ligase Catalyzes the Polyubiquitination of Alpha4 (α4), a Regulatory Subunit of Protein Phosphatase 2A (PP2A)

Huang²,

Zaghlula

et al. 2013

Journal of Biological Chemistry

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“…Because OA might induce inhibition of other phosphatases, in addition to PPA2, cells were treated with fostriecin, which has shown specific inhibition of PPA2 at low concentrations. 29 Figure 5B). Taken together, these results suggested that LDL modulate pHSP27 levels via PPA2.…”

Section: Protein Phosphatase A2 Was Involved In Hsp27 Dephosphorylatimentioning

confidence: 95%

Low-Density Lipoproteins Induce Heat Shock Protein 27 Dephosphorylation, Oligomerization, and Subcellular Relocalization in Human Vascular Smooth Muscle Cells

García-Arguinzonis

Padró

Lugano

et al. 2010

ATVB

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Objective-High levels of circulating low-density lipoproteins (LDL) are a major atherosclerotic risk factor. The effects of intimal LDL on vascular smooth muscle cell (VSMC) phenotype and function during plaque remodeling and vascular repair are not fully understood. We have investigated whether exposure of VSMC to LDL induces changes on the proteomic profile of the heat shock protein (HSP) family-molecular chaperones involved in atherosclerosis. Methods & Results-2D electrophoresis demonstrates that LDL modifies the proteomic profile of HSP27 (HSPB1).Western blot analysis evidenced a significant HSP27 dephosphorylation after exposure of cells to native LDL (nLDL) and aggregated-LDL (agLDL) for 24 hours (PϽ0.05). Dephosphorylation of HSP27 was not related to changes in p38 MAPK phosphorylation. Both nLDL and agLDL induced relocalization of unphosphorylated HSP27 to the tip of actin stress fibers and focal adhesion structures in VSMC. During cell adhesion, phospho-HSP27 was located at the cell surface contact region in LDL-treated cells, whereas it remained cytosolic in control cells. Immunohistochemistry studies showed that phosphorylated HSP27 is rarely found in lipid-rich areas of atherosclerotic plaques in human coronary arteries. (oxidation, glycosylation, aggregation). Modified LDL have been associated with changes in endothelial function, 2 as well as with migration, proliferation, and apoptosis of vascular smooth muscle cells (VSMCs). 3 Migration and proliferation of VSMCs, as well as extracellular matrix production and catabolism, are important events in the development of atherosclerosis and arterial remodeling. 4 VSMCs acquire or lose various functions to be able to fulfill the requirements for intimal remodeling. 5 Previous studies from our group demonstrated that LDL induce changes on VSMC gene expression and phenotype, leading to alterations in vascular function. 6 -8 We have recently demonstrated that aggregated LDL (agLDL) impair VSMC migration and wound repair after injury. 9 In response to stress, cells activate cytoprotective pathways. Heat shock proteins (HSP) are molecular chaperones that have the ability to protect proteins from damage induced by factors such as free radicals, heat, or ischemia. It has been demonstrated that HSP are highly expressed in atherosclerotic lesions of humans, rabbits, and apolipoprotein E-deficient mice. 10 Interestingly, HSP90 (HSP90AA1) expression is induced in VSMC by oxidative stress 11 and plays a role in the maintenance of endothelial barrier integrity by binding endothelial nitric oxide synthase and guanylyl cyclase (reviewed in Antonova et al 12 ). Overexpression of HSP70 (HSPA1A) in mouse heart increases resistance to ischemic injury. 13 Small HSP can also protect against ischemic injury in cardiomyocytes. 14 Among small HSP, HSP27 (HSPB1) acts as a molecular chaperone in vitro 15 and is also involved in F-actin assembly. 16,17 In smooth muscle, HSP27 is constitutively expressed and, when phosphorylated, colocalizes with contractile proteins. 18 In th...

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“…MID1 is a microtubule-associated E3 ligase that targets the phosphatase PP2A for degradation [3], the microtubule association of MID1 is regulated by phosphorylation [4], active transport of MID1 along microtubules is regulated by PP2A [5], and MID1 localizes specific mRNA molecules to microtubules [6,7]. MID1 indeed is a key player in development and, as briefly described below, also in disease [6].…”

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confidence: 99%

Mechanism of midline defect‐causing mutation P151L in MID1 revealed

Nicholson

2017

The FEBS Journal

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The structural complexity of a developing organism requires tight spatiotemporal control of cell-to-cell communication. This regulated intercellular messaging connects to intracellular signaling pathways that govern fundamental biological processes that facilitate organism development, such as transcription, translation, cell division, and cell migration. Common themes in elucidated molecular pathways involved in organism development include transient signals generated by opposing kinase and phosphatase activities, and by the rivaling processes of protein production and ubiquitinmediated proteasomal degradation [1]. Kinases, phosphatases, and E3 ligases are factors that play particularly critical roles in orchestrating the formation of the exquisite structural order of multicellular organisms. Additionally, new imaging technologies are revealing the importance of factors that induce mRNA localization to achieve spatially polarized protein expression in specific stages of organism development [2].The human protein MID1, which is known to play a central role in development along the ventral midline region, touches on all of these types of factors that are central to the regulation of developmental processes. MID1 is a microtubule-associated E3 ligase that targets the phosphatase PP2A for degradation [3], the microtubule association of MID1 is regulated by phosphorylation [4], active transport of MID1 along microtubules is regulated by PP2A [5], and MID1 localizes specific mRNA molecules to microtubules [6,7]. MID1 indeed is a key player in development and, as briefly described below, also in disease [6].In this issue of The FEBS Journal, Wright et al.[8] characterize the biochemical effects and elucidate the structural mechanism of a MID1 loss-of-function mutant, P151L. The P151L substitution is one of several MID1 mutations that cause midline birth defects associated with the monogenic disorder X-linked opitz G syndrome (XLOS). MID1 contains six structural domains, including a RING domain and two B-box domains (B-box1 and B-box2) that act synergistically to ubiquitinate the catalytic subunit of PP2A (PP2Ac), thereby targeting this master regulator of cellular processes to proteasomal degradation. Association of MID1 with PP2Ac requires the PP2A regulatory subunit a4, which serves as an adapter protein that binds via distinct surfaces to MID1 and to PP2Ac to form the MID1-a4-PP2Ac complex [9]. The P151L mutation is located in B-box1, the MID1 domain known to mediate interaction with a4 [10]. In this issue, Wright et al.[8] demonstrate through NMR and biochemical studies that the P151L mutant retains the overall tertiary structure of the B-box1 domain and preserves its E3 ligase activity, but loses its ability to bind to a4. This loss of interaction between B-box1 and a4 manifests biochemically as a loss of targeting and polyubiquitination of a4. The P151L mutation resides at the beginning of loop2 in B-box1, and the authors propose a structural mechanism in which the substituted Leu residue removes the conformatio...

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Active Transport of the Ubiquitin Ligase MID1 along the Microtubules Is Regulated by Protein Phosphatase 2A

Cited by 39 publications

References 36 publications

The MID1 E3 Ligase Catalyzes the Polyubiquitination of Alpha4 (α4), a Regulatory Subunit of Protein Phosphatase 2A (PP2A)

The MID1 E3 Ligase Catalyzes the Polyubiquitination of Alpha4 (α4), a Regulatory Subunit of Protein Phosphatase 2A (PP2A)

Low-Density Lipoproteins Induce Heat Shock Protein 27 Dephosphorylation, Oligomerization, and Subcellular Relocalization in Human Vascular Smooth Muscle Cells

Mechanism of midline defect‐causing mutation P151L in MID1 revealed

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