Sandbox Reserved 1777: Difference between revisions

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[[Image:Screen Shot 2023-04-16 at 7.30.09 PM.jpeg|650px|thumb|<font size="2"><div style="text-align: center;">'''Figure 1'''. Schematic representation of RAS/RAF/MEK/ERK pathway after assembly of SHOC2-PP1C-MRAS complex. </div></font>]]

After activation via an extracellular growth factor, the RAS-GTPase enzyme binds GTP, which recruits RAF to the cell membrane. [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> is a kinase that stimulates a signaling cascade by phosphorylation of MAPK (also known as MEK in mammals), which activates downstream proteins such as ERK1 and ERK2~~, which~~ subsequently activate nuclear transcription factors and kinases, as seen in Figure 1. 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 (Figure 1) 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>.

After activation via an extracellular growth factor, the RAS-GTPase enzyme binds GTP, which recruits RAF to the cell membrane. [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> is a kinase that stimulates a signaling cascade by phosphorylation of MAPK (also known as MEK in mammals), which activates downstream proteins such as ERK1 and ERK2. ERK1 and ERK2 subsequently activate nuclear transcription factors and kinases, as seen in Figure 1. 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 (Figure 1) 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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[[Image:Noonan syndrome figure.jpg|500px|right|thumb|<font size="2"><div style="text-align: center;">'''Figure 4'''. Common Symptoms of Noonan Syndrome. </div></font>]]

The SHOC2-MRAS~~-PP1C~~ complex's key role in the regulation of the MAPK-RAF pathway means that minor changes in its structure or function can have drastic biological consequences. Unregulated activation of the MAPK pathway is the cause of several human cancers due to unchecked cell division and proliferation<ref name="Kwan" />. Mutations that stabilize the interactions of the SMP complex enhance PP1C phosphatase activity <Ref name="Jajian" />, leading to increased RAF signaling and accelerated cell division. Most SHOC2 or PP1C mutations alter residues that are the direct contact points, stabilizing the interaction between the two proteins. Mutations to MRAS result in persistent binding of GTP, leading to consistent activation of the cell signaling pathway<ref name="Kwan" />.

The SHOC2-PP1C-MRAS complex's key role in the regulation of the MAPK-RAF pathway means that minor changes in its structure or function can have drastic biological consequences. Unregulated activation of the MAPK pathway is the cause of several human cancers due to unchecked cell division and proliferation<ref name="Kwan" />. Mutations that stabilize the interactions of the SMP complex enhance PP1C phosphatase activity <Ref name="Jajian" />, leading to increased RAF signaling and accelerated cell division. Most SHOC2 or PP1C mutations alter residues that are the direct contact points, stabilizing the interaction between the two proteins. Mutations to MRAS result in persistent binding of GTP, leading to consistent activation of the cell signaling pathway<ref name="Kwan" />.

The unregulated MAPK pathway is also responsible for a multitude of developmental disorders commonly known as [https://dceg.cancer.gov/research/what-we-study/rasopathies#:~:text=RASopathies%20are%20a%20group%20of,to%20grow%20and%20work%20properly. RASopathies] <Ref name="Lavoie" />. One RASopathy caused by the mutation of a RAF kinase is known as [https://www.mayoclinic.org/diseases-conditions/noonan-syndrome/symptoms-causes/syc-20354422 Noonan Syndrome] (NS), which enhances complex formation by stabilizing the interactions of each member <ref name="Kwan" />. NS is a genetic disorder that can prevent normal development during the neonatal period, leading to difficulties with feeding and a failure to thrive<Ref name= 'van der Burgt'> van der Burgt, I. Noonan syndrome. Orphanet J Rare Dis 2, 4 (2007). doi: 10.1186/1750-1172-2-4 [https://doi.org/10.1186/1750-1172-2-4. DOI: 10.1186/1750-1172-2-4]. </Ref>. The characteristic features of NS become more evident during infancy and childhood. NS patients often have atypical facial appearance, short stature, heart defects, and other physical problems (Figure 4)<ref name="van der Burgt" />.

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@@ Line 7: / Line 7: @@
 [[Image:Screen Shot 2023-04-16 at 7.30.09 PM.jpeg|650px|thumb|<font size="2"><div style="text-align: center;">'''Figure 1'''. Schematic representation of RAS/RAF/MEK/ERK pathway after assembly of SHOC2-PP1C-MRAS complex. </div></font>]]
-After activation via an extracellular growth factor, the RAS-GTPase enzyme binds GTP, which recruits RAF to the cell membrane. [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> is a kinase that stimulates a signaling cascade by phosphorylation of MAPK (also known as MEK in mammals), which activates downstream proteins such as ERK1 and ERK2, which subsequently activate nuclear transcription factors and kinases, as seen in Figure 1. 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 (Figure 1) 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>.
+After activation via an extracellular growth factor, the RAS-GTPase enzyme binds GTP, which recruits RAF to the cell membrane. [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> is a kinase that stimulates a signaling cascade by phosphorylation of MAPK (also known as MEK in mammals), which activates downstream proteins such as ERK1 and ERK2. ERK1 and ERK2 subsequently activate nuclear transcription factors and kinases, as seen in Figure 1. 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 (Figure 1) 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>.
@@ Line 47: / Line 47: @@
 [[Image:Noonan syndrome figure.jpg|500px|right|thumb|<font size="2"><div style="text-align: center;">'''Figure 4'''. Common Symptoms of Noonan Syndrome. </div></font>]]
-The SHOC2-MRAS-PP1C complex's key role in the regulation of the MAPK-RAF pathway means that minor changes in its structure or function can have drastic biological consequences. Unregulated activation of the MAPK pathway is the cause of several human cancers due to unchecked cell division and proliferation<ref name="Kwan" />. Mutations that stabilize the interactions of the SMP complex enhance PP1C phosphatase activity <Ref name="Jajian" />, leading to increased RAF signaling and accelerated cell division. Most SHOC2 or PP1C mutations alter residues that are the direct contact points, stabilizing the interaction between the two proteins. Mutations to MRAS result in persistent binding of GTP, leading to consistent activation of the cell signaling pathway<ref name="Kwan" />.
+The SHOC2-PP1C-MRAS complex's key role in the regulation of the MAPK-RAF pathway means that minor changes in its structure or function can have drastic biological consequences. Unregulated activation of the MAPK pathway is the cause of several human cancers due to unchecked cell division and proliferation<ref name="Kwan" />. Mutations that stabilize the interactions of the SMP complex enhance PP1C phosphatase activity <Ref name="Jajian" />, leading to increased RAF signaling and accelerated cell division. Most SHOC2 or PP1C mutations alter residues that are the direct contact points, stabilizing the interaction between the two proteins. Mutations to MRAS result in persistent binding of GTP, leading to consistent activation of the cell signaling pathway<ref name="Kwan" />.
 The unregulated MAPK pathway is also responsible for a multitude of developmental disorders commonly known as [https://dceg.cancer.gov/research/what-we-study/rasopathies#:~:text=RASopathies%20are%20a%20group%20of,to%20grow%20and%20work%20properly. RASopathies] <Ref name="Lavoie" />. One RASopathy caused by the mutation of a RAF kinase is known as [https://www.mayoclinic.org/diseases-conditions/noonan-syndrome/symptoms-causes/syc-20354422 Noonan Syndrome] (NS), which enhances complex formation by stabilizing the interactions of each member <ref name="Kwan" />.  NS is a genetic disorder that can prevent normal development during the neonatal period, leading to difficulties with feeding and a failure to thrive<Ref name= 'van der Burgt'> van der Burgt, I. Noonan syndrome. Orphanet J Rare Dis 2, 4 (2007). doi: 10.1186/1750-1172-2-4 [https://doi.org/10.1186/1750-1172-2-4. DOI: 10.1186/1750-1172-2-4]. </Ref>. The characteristic features of NS become more evident during infancy and childhood. NS patients often have atypical facial appearance, short stature, heart defects, and other physical problems (Figure 4)<ref name="van der Burgt" />.