Ras isoforms: signaling specificities in CD40 pathway
Abstract Background Ras are small cellular GTPases which regulate diverse cellular processes. It has three isoforms: H-Ras, K-Ras, and N-Ras. Owing to the N-terminus (1–165 residues) sequence homology these isoforms were thought to be functionally redundant. However, only K-Ras-deficient mice but no...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-01-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-019-0497-1 |
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| author | Arathi Nair Sushmita Chakraborty Late Anirban Banerji Ankita Srivastava Charudutta Navare Bhaskar Saha |
| author_facet | Arathi Nair Sushmita Chakraborty Late Anirban Banerji Ankita Srivastava Charudutta Navare Bhaskar Saha |
| author_sort | Arathi Nair |
| collection | DOAJ |
| description | Abstract Background Ras are small cellular GTPases which regulate diverse cellular processes. It has three isoforms: H-Ras, K-Ras, and N-Ras. Owing to the N-terminus (1–165 residues) sequence homology these isoforms were thought to be functionally redundant. However, only K-Ras-deficient mice but not H-Ras- and N-Ras-deficient mice show embryonic lethality. Similarly, mutations in a given Ras isoform are associated with a particular type of cancer. Moreover, we have previously reported that Ras isoforms perform unique functions in Leishmania major infection. Thus, Ras isoforms are implicated to have signaling and functional specificity but the mechanism remains to be elucidated. Result Using CD40 as a model receptor, we showed that depending on the strength of signaling, specific Ras isoforms are activated. Weak CD40 signal activates N-Ras, whereas strong signal activates H-Ras and K-Ras. Additionally, we showed that suppression of N-Ras expression reduced CD40-induced extracellular signal–regulated kinase-1/2 (ERK-1/2) activation and Interleukin (IL)-10 production; whereas suppression of H-Ras or K-Ras reduced CD40-induced p38 mitogen-activated protein kinase (p38MAPK) activation and IL-12 production. Furthermore, we showed that Ras isoforms have activator (GEF) specificity as weak CD40 signal-activated N-Ras requires Sos-1/2 whereas strong CD40 signal-activated H-Ras/K-Ras requires Ras-GRP as the guanine-nucleotide exchange factor (GEF) inducing ERK-1/2- or p38MAPK-mediated IL-10 or IL-12 productions, respectively, in macrophages. Silencing of syk reduced CD40-induced N-Ras activation but silencing of lyn inhibited H-Ras and K-Ras activation. In CD40 signaling, Ras isoforms also showed effector specificity; while H-Ras and K-Ras showed specificity for phosphatidyl inositol-3 kinase activation at high dose of CD40 stimulation, N-Ras primarily associated with Raf-1 at low dose of CD40 stimulation. Moreover, fractal analysis showed that functional site surface roughness for H-Ras (SurfaceFD = 2.39) and K-Ras (SurfaceFD = 2.39) are similar but significantly different from N-Ras (SurfaceFD = 2.25). Conclusion The activator and effector specificities of Ras isoforms in CD40 signaling indicated their differential involvement in CD40 pathway and in maintaining the reciprocity. Our observations reveal Ras-regulated signaling outcome and its potential for developing Ras isoform-targeted immunotherapy and prophylaxis. Graphical abstract |
| first_indexed | 2024-12-14T21:38:45Z |
| format | Article |
| id | doaj.art-6fd5380f2fdf4890a134d634b9ec5fce |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-14T21:38:45Z |
| publishDate | 2020-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-6fd5380f2fdf4890a134d634b9ec5fce2022-12-21T22:46:32ZengBMCCell Communication and Signaling1478-811X2020-01-0118111210.1186/s12964-019-0497-1Ras isoforms: signaling specificities in CD40 pathwayArathi Nair0Sushmita Chakraborty1Late Anirban Banerji2Ankita Srivastava3Charudutta Navare4Bhaskar Saha5National Centre for Cell ScienceNational Centre for Cell ScienceBioinformatics Centre, University of PuneNational Centre for Cell ScienceBioinformatics Centre, University of PuneNational Centre for Cell ScienceAbstract Background Ras are small cellular GTPases which regulate diverse cellular processes. It has three isoforms: H-Ras, K-Ras, and N-Ras. Owing to the N-terminus (1–165 residues) sequence homology these isoforms were thought to be functionally redundant. However, only K-Ras-deficient mice but not H-Ras- and N-Ras-deficient mice show embryonic lethality. Similarly, mutations in a given Ras isoform are associated with a particular type of cancer. Moreover, we have previously reported that Ras isoforms perform unique functions in Leishmania major infection. Thus, Ras isoforms are implicated to have signaling and functional specificity but the mechanism remains to be elucidated. Result Using CD40 as a model receptor, we showed that depending on the strength of signaling, specific Ras isoforms are activated. Weak CD40 signal activates N-Ras, whereas strong signal activates H-Ras and K-Ras. Additionally, we showed that suppression of N-Ras expression reduced CD40-induced extracellular signal–regulated kinase-1/2 (ERK-1/2) activation and Interleukin (IL)-10 production; whereas suppression of H-Ras or K-Ras reduced CD40-induced p38 mitogen-activated protein kinase (p38MAPK) activation and IL-12 production. Furthermore, we showed that Ras isoforms have activator (GEF) specificity as weak CD40 signal-activated N-Ras requires Sos-1/2 whereas strong CD40 signal-activated H-Ras/K-Ras requires Ras-GRP as the guanine-nucleotide exchange factor (GEF) inducing ERK-1/2- or p38MAPK-mediated IL-10 or IL-12 productions, respectively, in macrophages. Silencing of syk reduced CD40-induced N-Ras activation but silencing of lyn inhibited H-Ras and K-Ras activation. In CD40 signaling, Ras isoforms also showed effector specificity; while H-Ras and K-Ras showed specificity for phosphatidyl inositol-3 kinase activation at high dose of CD40 stimulation, N-Ras primarily associated with Raf-1 at low dose of CD40 stimulation. Moreover, fractal analysis showed that functional site surface roughness for H-Ras (SurfaceFD = 2.39) and K-Ras (SurfaceFD = 2.39) are similar but significantly different from N-Ras (SurfaceFD = 2.25). Conclusion The activator and effector specificities of Ras isoforms in CD40 signaling indicated their differential involvement in CD40 pathway and in maintaining the reciprocity. Our observations reveal Ras-regulated signaling outcome and its potential for developing Ras isoform-targeted immunotherapy and prophylaxis. Graphical abstracthttps://doi.org/10.1186/s12964-019-0497-1Ras isoformsCD40Signal transductionSpecificity |
| spellingShingle | Arathi Nair Sushmita Chakraborty Late Anirban Banerji Ankita Srivastava Charudutta Navare Bhaskar Saha Ras isoforms: signaling specificities in CD40 pathway Cell Communication and Signaling Ras isoforms CD40 Signal transduction Specificity |
| title | Ras isoforms: signaling specificities in CD40 pathway |
| title_full | Ras isoforms: signaling specificities in CD40 pathway |
| title_fullStr | Ras isoforms: signaling specificities in CD40 pathway |
| title_full_unstemmed | Ras isoforms: signaling specificities in CD40 pathway |
| title_short | Ras isoforms: signaling specificities in CD40 pathway |
| title_sort | ras isoforms signaling specificities in cd40 pathway |
| topic | Ras isoforms CD40 Signal transduction Specificity |
| url | https://doi.org/10.1186/s12964-019-0497-1 |
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