Sandbox Reserved 1777: Difference between revisions

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<StructureSection load='7pui' size='350' side='right' caption='SHOC2-PP1C-MRAS (PDB entry [[7pui]])' scene='95/952704/Smpcolored/1'>
<StructureSection load='7pui' size='350' side='right' caption='SHOC2-PP1C-MRAS (PDB entry [[7pui]])' scene='95/952704/Smpcolored/1'>
=Introduction=
=Introduction=
[[Image: Image 4-3-23 at 10.02 AM.jpeg|300px|right|thumb|<font size="3.5"><div style="text-align: center;">Schematic representation of SHOC2-PP1C-MRAS pathway after all domains are bound together. </div></font>]]
SHOC2-PP1C-MRAS is a human enzyme that is involved in regulating cell proliferation and division <Ref name='Astrain'>Bernal Astrain G, Nikolova M, Smith MJ. Functional diversity in the RAS subfamily of small GTPases. Biochem Soc Trans. 2022 Apr 29;50(2):921-933. doi: 10.1042/BST20211166. [https://doi.org/10.1042/BST20211166. DOI:10.1042/BST20211166] </Ref>. The enzyme is involved in the vast RAS-MAPK pathway, which is initially activated by an extracellular growth factor binding to a membrane bound RAS [https://www.mechanobio.info/what-is-mechanosignaling/what-are-small-gtpases/what-are-ras-gtpases/. GTPase] such as HRAS, NRAS, or KRAS. [https://www.frontiersin.org/articles/10.3389/fonc.2019.01088/full#:~:text=In%20human%20cells%2C%20three%20closely,proliferation%20and%20survival%20among%20others. RAS-GTPases] are a family of proteins that work by functioning as molecular switches. This occurs from the protein alternating between binding GTP to be active and GDP to be inactive <ref name="Astrain" />. After activation via an extracellular growth factor, the RAS-GTPase enzyme binds GTP, which activates [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311149/#:~:text=Full%20activation%20of%20Raf%20requires,plasma%20membrane%20(Roy%20et%20al RAF]<Ref name='Molina'>Molina JR, Adjei AA. The Ras/Raf/MAPK pathway. J Thorac Oncol. 2006 Jan;1(1):7-9. [https://doi.org/10.1016/S1556-0864(15)31506-9. DOI:10.1016/S1556-0864(15)31506-9]. </Ref> by phosphorylating the serine 259 residue. RAF triggers a series of downstream signaling pathways including MEK and ERK. The Ras/Raf/MEK/ERK pathway is a critical signaling cascade for activating transcription factors and regulating gene expression<Ref name='Li'>Li, L., Zhao, G. D., Shi, Z. et. al.The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncology letters, 12(5), 3045–3050. [https://doi.org/10.3892/ol.2016.5110. DOI:10.3892/ol.2016.5110]. </Ref>.  
SHOC2-PP1C-MRAS is a human enzyme that is involved in regulating cell proliferation and division <Ref name='Astrain'>Bernal Astrain G, Nikolova M, Smith MJ. Functional diversity in the RAS subfamily of small GTPases. Biochem Soc Trans. 2022 Apr 29;50(2):921-933. doi: 10.1042/BST20211166. [https://doi.org/10.1042/BST20211166. DOI:10.1042/BST20211166] </Ref>. The enzyme is involved in the vast RAS-MAPK pathway, which is initially activated by an extracellular growth factor binding to a membrane bound RAS [https://www.mechanobio.info/what-is-mechanosignaling/what-are-small-gtpases/what-are-ras-gtpases/. GTPase] such as HRAS, NRAS, or KRAS. [https://www.frontiersin.org/articles/10.3389/fonc.2019.01088/full#:~:text=In%20human%20cells%2C%20three%20closely,proliferation%20and%20survival%20among%20others. RAS-GTPases] are a family of proteins that work by functioning as molecular switches. This occurs from the protein alternating between binding GTP to be active and GDP to be inactive <ref name="Astrain" />. After activation via an extracellular growth factor, the RAS-GTPase enzyme binds GTP, which activates [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311149/#:~:text=Full%20activation%20of%20Raf%20requires,plasma%20membrane%20(Roy%20et%20al RAF]<Ref name='Molina'>Molina JR, Adjei AA. The Ras/Raf/MAPK pathway. J Thorac Oncol. 2006 Jan;1(1):7-9. [https://doi.org/10.1016/S1556-0864(15)31506-9. DOI:10.1016/S1556-0864(15)31506-9]. </Ref> by phosphorylating the serine 259 residue. RAF triggers a series of downstream signaling pathways including MEK and ERK. The Ras/Raf/MEK/ERK pathway is a critical signaling cascade for activating transcription factors and regulating gene expression<Ref name='Li'>Li, L., Zhao, G. D., Shi, Z. et. al.The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC. Oncology letters, 12(5), 3045–3050. [https://doi.org/10.3892/ol.2016.5110. DOI:10.3892/ol.2016.5110]. </Ref>.  


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=Mechanism=
=Mechanism=
[[Image: Image 4-3-23 at 10.02 AM.jpeg|300px|right|thumb|<font size="3.5"><div style="text-align: center;">Schematic representation of SHOC2-PP1C-MRAS pathway after all domains are bound together. </div></font>]]


Once the SMP complex comes together, it plays a key role in regulating the activation of the RAF and MAPK pathway. To do so, PP1C, enhanced through the interactions with SHOC2 and MRAS, dephosphorylates a specific phosphoserine on RAF kinases. Doing so regulates cell growth, survival, proliferation, and differentiation <Ref name='Lavoie'>Lavoie, H., Therrien, M. Structural keys unlock RAS–MAPK cellular signalling pathway. Nature 609, 248-249 (2022). doi: 10.1038/d41586-022-02189-7. [https://doi.org/10.1038/d41586-022-02189-7. DOI:10.1038/d41586-022-02189-7]. </Ref>.  
Once the SMP complex comes together, it plays a key role in regulating the activation of the RAF and MAPK pathway. To do so, PP1C, enhanced through the interactions with SHOC2 and MRAS, dephosphorylates a specific phosphoserine on RAF kinases. Doing so regulates cell growth, survival, proliferation, and differentiation <Ref name='Lavoie'>Lavoie, H., Therrien, M. Structural keys unlock RAS–MAPK cellular signalling pathway. Nature 609, 248-249 (2022). doi: 10.1038/d41586-022-02189-7. [https://doi.org/10.1038/d41586-022-02189-7. DOI:10.1038/d41586-022-02189-7]. </Ref>.  
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