14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway
The cAMP/PKA and mitogen-activated protein kinase (MAPK) signaling cascade control many cellular processes and are highly regulated for optimal cellular responses upon external stimuli. Phosphodiesterase 8A (PDE8A) is an important regulator that inhibits signaling via cAMP-dependent PKA by hydrolyzi...
| Main Authors: | , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2024
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/178406 |
| _version_ | 1824455883153735680 |
|---|---|
| author | Mukherjee, Soumita Roy, Somesh Mukherjee, Shruti Harikishore, Amaravadhi Bhunia, Anirban Mandal, Atin K. |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Mukherjee, Soumita Roy, Somesh Mukherjee, Shruti Harikishore, Amaravadhi Bhunia, Anirban Mandal, Atin K. |
| author_sort | Mukherjee, Soumita |
| collection | NTU |
| description | The cAMP/PKA and mitogen-activated protein kinase (MAPK) signaling cascade control many cellular processes and are highly regulated for optimal cellular responses upon external stimuli. Phosphodiesterase 8A (PDE8A) is an important regulator that inhibits signaling via cAMP-dependent PKA by hydrolyzing intracellular cAMP pool. Conversely, PDE8A activates the MAPK pathway by protecting CRAF/Raf1 kinase from PKA-mediated inhibitory phosphorylation at Ser259 residue, a binding site of scaffold protein 14-3-3. It still remains enigmatic as to how the cross-talk involving PDE8A regulation influences cAMP/PKA and MAPK signaling pathways. Here, we report that PDE8A interacts with 14-3-3ζ in both yeast and mammalian system, and this interaction is enhanced upon the activation of PKA, which phosphorylates PDE8A's Ser359 residue. Biophysical characterization of phospho-Ser359 peptide with 14-3-3ζ protein further supports their interaction. Strikingly, 14-3-3ζ reduces the catalytic activity of PDE8A, which upregulates the cAMP/PKA pathway while the MAPK pathway is downregulated. Moreover, 14-3-3ζ in complex with PDE8A and cAMP-bound regulatory subunit of PKA, RIα, delays the deactivation of PKA signaling. Our results define 14-3-3ζ as a molecular switch that operates signaling between cAMP/PKA and MAPK by associating with PDE8A. |
| first_indexed | 2025-02-19T03:45:17Z |
| format | Journal Article |
| id | ntu-10356/178406 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:45:17Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1784062024-06-24T15:32:13Z 14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway Mukherjee, Soumita Roy, Somesh Mukherjee, Shruti Harikishore, Amaravadhi Bhunia, Anirban Mandal, Atin K. School of Biological Sciences Medicine, Health and Life Sciences CRAF kinase Phosphodiesterase The cAMP/PKA and mitogen-activated protein kinase (MAPK) signaling cascade control many cellular processes and are highly regulated for optimal cellular responses upon external stimuli. Phosphodiesterase 8A (PDE8A) is an important regulator that inhibits signaling via cAMP-dependent PKA by hydrolyzing intracellular cAMP pool. Conversely, PDE8A activates the MAPK pathway by protecting CRAF/Raf1 kinase from PKA-mediated inhibitory phosphorylation at Ser259 residue, a binding site of scaffold protein 14-3-3. It still remains enigmatic as to how the cross-talk involving PDE8A regulation influences cAMP/PKA and MAPK signaling pathways. Here, we report that PDE8A interacts with 14-3-3ζ in both yeast and mammalian system, and this interaction is enhanced upon the activation of PKA, which phosphorylates PDE8A's Ser359 residue. Biophysical characterization of phospho-Ser359 peptide with 14-3-3ζ protein further supports their interaction. Strikingly, 14-3-3ζ reduces the catalytic activity of PDE8A, which upregulates the cAMP/PKA pathway while the MAPK pathway is downregulated. Moreover, 14-3-3ζ in complex with PDE8A and cAMP-bound regulatory subunit of PKA, RIα, delays the deactivation of PKA signaling. Our results define 14-3-3ζ as a molecular switch that operates signaling between cAMP/PKA and MAPK by associating with PDE8A. Published version This work was supported by grant from STBT-WB [1811(Sanc.)/STBT-11012(12)/23/2020-BT SEC] to A. K. M. and funding from Bose Institute Intramural fund. Soumita Mukherjee is supported by postdoctoral fellowship from Science and Engineering Research Board (SERB), Government of India. Soumita Mukherjee is grateful for the financial support from the DBT-RA Program in Biotechnology and Life Sciences. S. R. and Sh. M. thank DBT and CSIR for fellowships, respectively. 2024-06-18T07:06:52Z 2024-06-18T07:06:52Z 2024 Journal Article Mukherjee, S., Roy, S., Mukherjee, S., Harikishore, A., Bhunia, A. & Mandal, A. K. (2024). 14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway. Journal of Biological Chemistry, 300(3), 105725-. https://dx.doi.org/10.1016/j.jbc.2024.105725 0021-9258 https://hdl.handle.net/10356/178406 10.1016/j.jbc.2024.105725 38325743 2-s2.0-85186347354 3 300 105725 en Journal of Biological Chemistry © 2024 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). application/pdf |
| spellingShingle | Medicine, Health and Life Sciences CRAF kinase Phosphodiesterase Mukherjee, Soumita Roy, Somesh Mukherjee, Shruti Harikishore, Amaravadhi Bhunia, Anirban Mandal, Atin K. 14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway |
| title | 14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway |
| title_full | 14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway |
| title_fullStr | 14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway |
| title_full_unstemmed | 14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway |
| title_short | 14-3-3 interaction with phosphodiesterase 8A sustains PKA signaling and downregulates the MAPK pathway |
| title_sort | 14 3 3 interaction with phosphodiesterase 8a sustains pka signaling and downregulates the mapk pathway |
| topic | Medicine, Health and Life Sciences CRAF kinase Phosphodiesterase |
| url | https://hdl.handle.net/10356/178406 |
| work_keys_str_mv | AT mukherjeesoumita 1433interactionwithphosphodiesterase8asustainspkasignalinganddownregulatesthemapkpathway AT roysomesh 1433interactionwithphosphodiesterase8asustainspkasignalinganddownregulatesthemapkpathway AT mukherjeeshruti 1433interactionwithphosphodiesterase8asustainspkasignalinganddownregulatesthemapkpathway AT harikishoreamaravadhi 1433interactionwithphosphodiesterase8asustainspkasignalinganddownregulatesthemapkpathway AT bhuniaanirban 1433interactionwithphosphodiesterase8asustainspkasignalinganddownregulatesthemapkpathway AT mandalatink 1433interactionwithphosphodiesterase8asustainspkasignalinganddownregulatesthemapkpathway |