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Stress responses from the endoplasmic reticulum in cancer.

Kato H, Nishitoh H - Front Oncol (2015)

Bottom Line: The UPR also contributes to the regulation of various intracellular signaling pathways such as calcium signaling and lipid signaling.More recently, the mitochondria-associated ER membrane (MAM), which is a site of close contact between the ER and mitochondria, has been shown to function as a platform for various intracellular stress responses including apoptotic signaling, inflammatory signaling, the autophagic response, and the UPR.In this review, we discuss recent research on the roles of stress responses from the ER, including the MAM.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki , Miyazaki , Japan.

ABSTRACT
The endoplasmic reticulum (ER) is a dynamic organelle that is essential for multiple cellular functions. During cellular stress conditions, including nutrient deprivation and dysregulation of protein synthesis, unfolded/misfolded proteins accumulate in the ER lumen, resulting in activation of the unfolded protein response (UPR). The UPR also contributes to the regulation of various intracellular signaling pathways such as calcium signaling and lipid signaling. More recently, the mitochondria-associated ER membrane (MAM), which is a site of close contact between the ER and mitochondria, has been shown to function as a platform for various intracellular stress responses including apoptotic signaling, inflammatory signaling, the autophagic response, and the UPR. Interestingly, in cancer, these signaling pathways from the ER are often dysregulated, contributing to cancer cell metabolism. Thus, the signaling pathway from the ER may be a novel therapeutic target for various cancers. In this review, we discuss recent research on the roles of stress responses from the ER, including the MAM.

No MeSH data available.


Related in: MedlinePlus

ER-mitochondrion tethering. In mammalian cells, four types of molecular bridges for ER-mitochondrion tethering have been identified. ER-resident MFN2 interacts with mitochondrial MFN1 and MFN2. The ER calcium channel IP3R associates with the mitochondrial calcium channel VDAC1 through GRP75. The ER protein Bap31 connects with the mitochondrial protein Fis1. The ER protein VAPB interacts with the mitochondrial protein PTPIP51. Indicated MAM-resident proteins and complexes regulate various signaling pathway from MAM as described in figure.
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Figure 2: ER-mitochondrion tethering. In mammalian cells, four types of molecular bridges for ER-mitochondrion tethering have been identified. ER-resident MFN2 interacts with mitochondrial MFN1 and MFN2. The ER calcium channel IP3R associates with the mitochondrial calcium channel VDAC1 through GRP75. The ER protein Bap31 connects with the mitochondrial protein Fis1. The ER protein VAPB interacts with the mitochondrial protein PTPIP51. Indicated MAM-resident proteins and complexes regulate various signaling pathway from MAM as described in figure.

Mentions: It has been observed that approximately 5–20% of the mitochondrial surface directly contacts the ER (19, 20). This site of close contact between the ER and mitochondria is called the mitochondria-associated ER membrane (MAM) and is formed by several molecular bridges. The mitochondrial outer membrane proteins mitofusin 1 and 2 (MFN1 and MFN2) are required for mitochondrial fusion. MFN1 contributes to mitochondrial docking and fusion, whereas MFN2 stabilizes associations between mitochondria. This maintenance of mitochondrial morphology is regulated by hetero-oligomeric MFN complexes on the mitochondrial outer membrane. Interestingly, MFN2 is also located on the ER membrane and forms homotypic or heterotypic complexes with mitochondrial MFNs, resulting in an interaction between the ER and mitochondria (21) (Figure 2). Acting as a similar molecular bridge, the inositol triphosphate receptor (IP3R) on the ER indirectly interacts with the mitochondrial outer membrane-resident voltage-dependent anion channel 1 (VDAC1) via the cytosolic chaperone glucose-regulated protein 75 (GRP75) (22). In addition, recent reports have demonstrated that the B-cell receptor-associated protein 31 (Bap31)-mitochondrial Fission-1 homolog (Fis1) complex (23) and vesicle-associated membrane protein-associated protein B (VAPB)-protein-tyrosine phosphatase interacting protein 51 (PTPIP51) complex act as tethering complexes for the ER-mitochondrion bridge (24) (Figure 2).


Stress responses from the endoplasmic reticulum in cancer.

Kato H, Nishitoh H - Front Oncol (2015)

ER-mitochondrion tethering. In mammalian cells, four types of molecular bridges for ER-mitochondrion tethering have been identified. ER-resident MFN2 interacts with mitochondrial MFN1 and MFN2. The ER calcium channel IP3R associates with the mitochondrial calcium channel VDAC1 through GRP75. The ER protein Bap31 connects with the mitochondrial protein Fis1. The ER protein VAPB interacts with the mitochondrial protein PTPIP51. Indicated MAM-resident proteins and complexes regulate various signaling pathway from MAM as described in figure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403295&req=5

Figure 2: ER-mitochondrion tethering. In mammalian cells, four types of molecular bridges for ER-mitochondrion tethering have been identified. ER-resident MFN2 interacts with mitochondrial MFN1 and MFN2. The ER calcium channel IP3R associates with the mitochondrial calcium channel VDAC1 through GRP75. The ER protein Bap31 connects with the mitochondrial protein Fis1. The ER protein VAPB interacts with the mitochondrial protein PTPIP51. Indicated MAM-resident proteins and complexes regulate various signaling pathway from MAM as described in figure.
Mentions: It has been observed that approximately 5–20% of the mitochondrial surface directly contacts the ER (19, 20). This site of close contact between the ER and mitochondria is called the mitochondria-associated ER membrane (MAM) and is formed by several molecular bridges. The mitochondrial outer membrane proteins mitofusin 1 and 2 (MFN1 and MFN2) are required for mitochondrial fusion. MFN1 contributes to mitochondrial docking and fusion, whereas MFN2 stabilizes associations between mitochondria. This maintenance of mitochondrial morphology is regulated by hetero-oligomeric MFN complexes on the mitochondrial outer membrane. Interestingly, MFN2 is also located on the ER membrane and forms homotypic or heterotypic complexes with mitochondrial MFNs, resulting in an interaction between the ER and mitochondria (21) (Figure 2). Acting as a similar molecular bridge, the inositol triphosphate receptor (IP3R) on the ER indirectly interacts with the mitochondrial outer membrane-resident voltage-dependent anion channel 1 (VDAC1) via the cytosolic chaperone glucose-regulated protein 75 (GRP75) (22). In addition, recent reports have demonstrated that the B-cell receptor-associated protein 31 (Bap31)-mitochondrial Fission-1 homolog (Fis1) complex (23) and vesicle-associated membrane protein-associated protein B (VAPB)-protein-tyrosine phosphatase interacting protein 51 (PTPIP51) complex act as tethering complexes for the ER-mitochondrion bridge (24) (Figure 2).

Bottom Line: The UPR also contributes to the regulation of various intracellular signaling pathways such as calcium signaling and lipid signaling.More recently, the mitochondria-associated ER membrane (MAM), which is a site of close contact between the ER and mitochondria, has been shown to function as a platform for various intracellular stress responses including apoptotic signaling, inflammatory signaling, the autophagic response, and the UPR.In this review, we discuss recent research on the roles of stress responses from the ER, including the MAM.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Biochemistry and Molecular Biology, Department of Medical Sciences, University of Miyazaki , Miyazaki , Japan.

ABSTRACT
The endoplasmic reticulum (ER) is a dynamic organelle that is essential for multiple cellular functions. During cellular stress conditions, including nutrient deprivation and dysregulation of protein synthesis, unfolded/misfolded proteins accumulate in the ER lumen, resulting in activation of the unfolded protein response (UPR). The UPR also contributes to the regulation of various intracellular signaling pathways such as calcium signaling and lipid signaling. More recently, the mitochondria-associated ER membrane (MAM), which is a site of close contact between the ER and mitochondria, has been shown to function as a platform for various intracellular stress responses including apoptotic signaling, inflammatory signaling, the autophagic response, and the UPR. Interestingly, in cancer, these signaling pathways from the ER are often dysregulated, contributing to cancer cell metabolism. Thus, the signaling pathway from the ER may be a novel therapeutic target for various cancers. In this review, we discuss recent research on the roles of stress responses from the ER, including the MAM.

No MeSH data available.


Related in: MedlinePlus