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PMID:21968647
| Citation |
Jin, T, Ding, Q, Huang, H, Xu, D, Jiang, Y, Zhou, B, Li, Z, Jiang, X, He, J, Liu, W, Zhang, Y, Pan, Y, Wang, Z, Thomas, WG and Chen, Y (2012) PAQR10 and PAQR11 mediate Ras signaling in the Golgi apparatus. Cell Res. 22:661-76 |
|---|---|
| Abstract |
Ras plays a pivotal role in many cellular activities, and its subcellular compartmentalization provides spatial and temporal selectivity. Here we report a mode of spatial regulation of Ras signaling in the Golgi apparatus by two highly homologous proteins PAQR10 and PAQR11 of the progestin and AdipoQ receptors family. PAQR10 and PAQR11 are exclusively localized in the Golgi apparatus. Overexpression of PAQR10/PAQR11 stimulates basal and EGF-induced ERK phosphorylation and increases the expression of ERK target genes in a dose-dependent manner. Overexpression of PAQR10/PAQR11 markedly elevates Golgi localization of HRas, NRas and KRas4A, but not KRas4B. PAQR10 and PAQR11 can also interact with HRas, NRas and KRas4A, but not KRas4B. The increased Ras protein at the Golgi apparatus by overexpression of PAQR10/PAQR11 is in an active state. Consistently, knockdown of PAQR10 and PAQR11 reduces EGF-stimulated ERK phosphorylation and Ras activation at the Golgi apparatus. Intriguingly, PAQR10 and PAQR11 are able to interact with RasGRP1, a guanine nucleotide exchange protein of Ras, and increase Golgi localization of RasGRP1. The C1 domain of RasGRP1 is both necessary and sufficient for the interaction of RasGRP1 with PAQR10/PAQR11. The simulation of ERK phosphorylation by overexpressed PAQR10/PAQR11 is abrogated by downregulation of RasGRP1. Furthermore, differentiation of PC12 cells is significantly enhanced by overexpression of PAQR10/PAQR11. Collectively, this study uncovers a new paradigm of spatial regulation of Ras signaling in the Golgi apparatus by PAQR10 and PAQR11. |
| Links |
PubMed PMC3317553 Online version:10.1038/cr.2011.161 |
| Keywords |
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| edit table |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
|
part_of |
GO:0005794: Golgi apparatus |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
| GO:0005794: Golgi apparatus |
ECO:0000314: |
C |
Under the condition of serum starvation, RasGRP1 was predominantly diffusely distributed…with a small portion localized to the Golgi (Figure 5C). when PAQR10 or PAQR11 was coexpressed, the localization of RasGRP1 in the Golgi compartment was profoundly increased under unstimulated condition (Figure 5C). |
complete | ||||
| GO:0001934: positive regulation of protein phosphorylation |
ECO:0000314: |
P |
We found that the PAQR10/ PAQR11-induced ERK phosphorylation was inhibited by RasGRP1-specific siRNAs (Figure 5D). In Hela cells, RasGRP1-specific siRNA could also abrogate PAQR10/ PAQR11-mediated accumulation of GFP-RBD in the Golgi apparatus (Supplementary information, Figure S12) |
complete | ||||
|
involved_in |
GO:0001934: positive regulation of protein phosphorylation |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
|
involved_in |
GO:0045666: positive regulation of neuron differentiation |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
|
enables |
GO:0004672: protein kinase activity |
ECO:0000314: direct assay evidence used in manual assertion |
F |
Seeded From UniProt |
complete | |||
|
involved_in |
GO:0032880: regulation of protein localization |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
|
involved_in |
GO:0045860: positive regulation of protein kinase activity |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0005794: Golgi apparatus |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
| GO:0005794: Golgi apparatus |
ECO:0000314: |
C |
When transiently transfected into Hela cells, N-terminally-tagged human PAQR10 and PAQR11 were both restricted to the Golgi apparatus and colocalized with Golgin-97, a Golgi marker (Figure 1A). …we found that the staining pattern of endogenous PAQR11 overlapped well with Golgin- 97 in A549 cells, which express high levels of PAQR11 (Figure 1B). |
complete | ||||
| GO:0045860: positive regulation of protein kinase activity |
ECO:0000314: |
P |
In HEK293T cells, overexpression of PAQR10 or PAQR11 dose-dependently increased the phosphorylation of ERK (Figure 1C). …the phosphorylation levels of ERK and p90RSK, a cytosolic target of ERK [40], were markedly reduced when both PAQR10 and PAQR11 were silenced (Figure 4A). |
complete | ||||
| GO:0032880: regulation of protein localization |
ECO:0000314: |
P |
when coexpressed with Flag-tagged PAQR10 or PAQR11, the localization of HRas in the Golgi apparatus was significantly increased with a clear colocalization with PAQR10/PAQR11 and Golgin-97 (Figure 2A). Overexpression of PAQR10/PAQR11 also markedly increased Golgi localization of NRas and KRas4A (Figure2B and 2C). In MDCK cells, PAQR10 also elevated Golgi localization of HRas, NRas and KRas4A, but not KRas4B (Supplementary information, Figure S7). (summarized in Figure 2E). |
complete | ||||
| GO:0004672: protein kinase activity |
ECO:0000314: |
F |
In HEK293T cells, overexpression of PAQR10 or PAQR11 dose-dependently increased the phosphorylation of ERK (Figure 1C). |
complete | ||||
| GO:0045666: positive regulation of neuron differentiation |
ECO:0000314: |
P |
When PAQR10 or PAQR11 was expressed in PC12 cells, either of them could significantly stimulate neurite outgrowth (Figure 7), a marker of PC12 cell differentiation. |
complete | ||||
|
involved_in |
GO:0045666: positive regulation of neuron differentiation |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
|
enables |
GO:0004672: protein kinase activity |
ECO:0000314: direct assay evidence used in manual assertion |
F |
Seeded From UniProt |
complete | |||
|
involved_in |
GO:0032880: regulation of protein localization |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
|
involved_in |
GO:0046579: positive regulation of Ras protein signal transduction |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
| GO:0045860: positive regulation of protein kinase activity |
ECO:0000314: |
P |
In HEK293T cells, overexpression of PAQR10 or PAQR11 dose-dependently increased the phosphorylation of ERK (Figure 1C). …the phosphorylation levels of ERK and p90RSK, a cytosolic target of ERK [40], were markedly reduced when both PAQR10 and PAQR11 were silenced (Figure 4A). |
complete | ||||
| GO:0046579: positive regulation of Ras protein signal transduction |
ECO:0000314: |
P |
We also examined the expression levels of a few target genes downstream of ERK signaling, including c-Fos, JunB and Egr-1 . Consistently, overexpression of PAQR10 elevated the expression levels of these genes in a dose-dependent manner (Figure 1Ewe found that PAQR10-activated ERK phosphorylation was abrogated by inhibitors that were specific for the Ras signaling cascade (Figure 1F). The PAQR10- induced transcription of Egr-1 was blocked by GFPRBD and PD98059 (Supplementary information, Figure S5 and 7B). |
complete | ||||
| GO:0032880: regulation of protein localization |
ECO:0000314: |
P |
when coexpressed with Flag-tagged PAQR10 or PAQR11, the localization of HRas in the Golgi apparatus was significantly increased with a clear colocalization with PAQR10/PAQR11 and Golgin-97 (Figure 2A). Overexpression of PAQR10/PAQR11 also markedly increased Golgi localization of NRas and KRas4A (Figure2B and 2C). In MDCK cells, PAQR10 also elevated Golgi localization of HRas, NRas and KRas4A, but not KRas4B (Supplementary information, Figure S7). (summarized in Figure 2E). |
complete | ||||
| GO:0004672: protein kinase activity |
ECO:0000314: |
F |
In HEK293T cells, overexpression of PAQR10 or PAQR11 dose-dependently increased the phosphorylation of ERK (Figure 1C). |
complete | ||||
| GO:0045666: positive regulation of neuron differentiation |
ECO:0000314: |
P |
When PAQR10 or PAQR11 was expressed in PC12 cells, either of them could significantly stimulate neurite outgrowth (Figure 7), a marker of PC12 cell differentiation. |
complete | ||||
|
involved_in |
GO:0045860: positive regulation of protein kinase activity |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
| GO:0005886: plasma membrane |
ECO:0000314: |
C |
When HRas was overexpressed in Hela cells, it was largely localized on the PM with a little Golgi localization (Figure 2A), |
complete | ||||
| GO:0005794: Golgi apparatus |
ECO:0000314: |
C |
When HRas was overexpressed in Hela cells, it was largely localized on the PM with a little Golgi localization (Figure 2A), (summarized in Figure 2E). |
complete | ||||
|
part_of |
GO:0005794: Golgi apparatus |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0005886: plasma membrane |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
|
part_of |
GO:0005794: Golgi apparatus |
ECO:0000314: direct assay evidence used in manual assertion |
C |
Seeded From UniProt |
complete | |||
| GO:0005794: Golgi apparatus |
ECO:0000314: |
C |
Overexpression of PAQR10/PAQR11 also markedly increased Golgi localization of NRas and KRas4A (Figure2B and 2C), (summarized in Figure 2E). |
complete | ||||
| GO:0072600: establishment of protein localization in Golgi |
ECO:0000315: |
P |
Figure 2B |
complete | ||||
| GO:0070849: response to epidermal growth factor stimulus |
ECO:0000314: |
P |
Overexpression of PAQR10 or PAQR11 also significantly enhanced and prolonged the phosphorylation of ERK upon EGF treatment (Figure 1D). |
complete | ||||
|
involved_in |
GO:0070849: response to epidermal growth factor |
ECO:0000314: direct assay evidence used in manual assertion |
P |
Seeded From UniProt |
complete | |||
See also
References
See Help:References for how to manage references in GONUTS.
p
- GO:0005886 ! plasma membrane
- GO:0001934 ! positive regulation of protein phosphorylation
- GO:0045666 ! positive regulation of neuron differentiation
- GO:0045860 ! positive regulation of protein kinase activity
- GO:0046579 ! positive regulation of Ras protein signal transduction
- GO:0004672 ! protein kinase activity
