K-Ras Lys-42 is crucial for its signaling, cell migration, and invasion
© 2018 Choi et al..
Ras proteins participate in multiple signal cascades, regulating crucial cellular processes, including cell survival, proliferation, and differentiation. We have previously reported that Ras proteins are modified by sumoylation and that Lys-42 plays an important role in mediating the modification. In the current study, we further investigated the role of Lys-42 in regulating cellular activities of K-Ras. Inducible expression of K-RasV12 led to the activation of downstream components, including c-RAF, MEK1, and extracellular signal-regulated kinases (ERKs), whereas expression of K-RasV12/R42 mutant compromised the activation of the RAF/MEK/ERK signaling axis. Expression of K-RasV12/R42 also led to reduced phosphorylation of several other protein kinases, including c-Jun N-terminal kinase (JNK), Chk2, and focal adhesion kinase (FAK). Significantly, K-RasV12/R42 expression inhibited cellular migration and invasion in vitro in multiple cell lines, including transformed pancreatic cells. Given that K-Ras plays a crucial role in mediating oncogenesis in the pancreas, we treated transformed pancreatic cells of both BxPC-3 and MiaPaCa-2 with 2-D08, a small ubiquitin-like modifier (SUMO) E2 inhibitor. Treatment with the compound inhibited cell migration in a concentration-dependent manner, which was correlated with a reduced level of K-Ras sumoylation. Moreover, 2-D08 suppressed expression of ZEB1 (a mesenchymal cell marker) with concomitant induction of ZO-1 (an epithelial cell marker). Combined, our studies strongly suggest that posttranslational modification(s), including sumoylation mediated by Lys-42, plays a crucial role in K-Ras activities in vivo.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:293 |
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| Enthalten in: |
The Journal of biological chemistry - 293(2018), 45 vom: 09. Nov., Seite 17574-17581 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Choi, Byeong Hyeok [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 19.03.2019 Date Revised 09.03.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1074/jbc.RA118.003723 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM288649184 |
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| 100 | 1 | |a Choi, Byeong Hyeok |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a K-Ras Lys-42 is crucial for its signaling, cell migration, and invasion |
| 264 | 1 | |c 2018 | |
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| 500 | |a Date Completed 19.03.2019 | ||
| 500 | |a Date Revised 09.03.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2018 Choi et al. | ||
| 520 | |a Ras proteins participate in multiple signal cascades, regulating crucial cellular processes, including cell survival, proliferation, and differentiation. We have previously reported that Ras proteins are modified by sumoylation and that Lys-42 plays an important role in mediating the modification. In the current study, we further investigated the role of Lys-42 in regulating cellular activities of K-Ras. Inducible expression of K-RasV12 led to the activation of downstream components, including c-RAF, MEK1, and extracellular signal-regulated kinases (ERKs), whereas expression of K-RasV12/R42 mutant compromised the activation of the RAF/MEK/ERK signaling axis. Expression of K-RasV12/R42 also led to reduced phosphorylation of several other protein kinases, including c-Jun N-terminal kinase (JNK), Chk2, and focal adhesion kinase (FAK). Significantly, K-RasV12/R42 expression inhibited cellular migration and invasion in vitro in multiple cell lines, including transformed pancreatic cells. Given that K-Ras plays a crucial role in mediating oncogenesis in the pancreas, we treated transformed pancreatic cells of both BxPC-3 and MiaPaCa-2 with 2-D08, a small ubiquitin-like modifier (SUMO) E2 inhibitor. Treatment with the compound inhibited cell migration in a concentration-dependent manner, which was correlated with a reduced level of K-Ras sumoylation. Moreover, 2-D08 suppressed expression of ZEB1 (a mesenchymal cell marker) with concomitant induction of ZO-1 (an epithelial cell marker). Combined, our studies strongly suggest that posttranslational modification(s), including sumoylation mediated by Lys-42, plays a crucial role in K-Ras activities in vivo | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a K-Ras | |
| 650 | 4 | |a Ras protein | |
| 650 | 4 | |a cell invasion | |
| 650 | 4 | |a cell migration | |
| 650 | 4 | |a domain structure | |
| 650 | 4 | |a lysine residue | |
| 650 | 4 | |a posttranslational modification (PTM) | |
| 650 | 4 | |a signaling | |
| 650 | 4 | |a sumoylation | |
| 650 | 4 | |a transformation | |
| 650 | 7 | |a 2',3',4'-trihydroxyflavone |2 NLM | |
| 650 | 7 | |a Flavones |2 NLM | |
| 650 | 7 | |a KRAS protein, human |2 NLM | |
| 650 | 7 | |a TJP1 protein, human |2 NLM | |
| 650 | 7 | |a Tjp1 protein, mouse |2 NLM | |
| 650 | 7 | |a ZEB1 protein, human |2 NLM | |
| 650 | 7 | |a ZEB1 protein, mouse |2 NLM | |
| 650 | 7 | |a Zinc Finger E-box-Binding Homeobox 1 |2 NLM | |
| 650 | 7 | |a Zonula Occludens-1 Protein |2 NLM | |
| 650 | 7 | |a Ubiquitin-Conjugating Enzymes |2 NLM | |
| 650 | 7 | |a EC 2.3.2.23 |2 NLM | |
| 650 | 7 | |a Checkpoint Kinase 2 |2 NLM | |
| 650 | 7 | |a EC 2.7.1.11 |2 NLM | |
| 650 | 7 | |a Focal Adhesion Kinase 1 |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a PTK2 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a Ptk2 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a CHEK2 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Chek2 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Extracellular Signal-Regulated MAP Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 650 | 7 | |a Hras protein, mouse |2 NLM | |
| 650 | 7 | |a EC 3.6.5.2 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins p21(ras) |2 NLM | |
| 650 | 7 | |a EC 3.6.5.2 |2 NLM | |
| 700 | 1 | |a Philips, Mark R |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Lou |e verfasserin |4 aut | |
| 700 | 1 | |a Dai, Wei |e verfasserin |4 aut | |
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