Sandbox Reserved 1767: Difference between revisions
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== Introduction == | == Introduction == | ||
<scene name='95/952695/Overall_image/2'>The SHOC2-MRAS-PP1C</scene> (SMP) holophosphatase complex functions as a key regulator of the [https://www.nature.com/scitable/topicpage/rtk-14050230/#:~:text=One%20of%20the%20most%20common,anchored%20to%20the%20plasma%20membrane. receptor tyrosine kinase (RTK)] signaling pathway by removing an inhibitory phosphate on the [https://www.sciencedirect.com/science/article/pii/S0167488907001164. RAF] family of proteins to allow for [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536342/. MAPK signaling].<ref name="Kwon">PMID: 35831509</ref> This interaction of the RTK-RAS pathway and the SMP complex drives cell proliferation.<ref name="Hauseman">PMID:35830882</ref> The SMP complex is made of three subunits, SHOC2, PP1C, and MRAS. Each of these subunits has a different shape that corresponds to its different function. <scene name='95/952695/Shoc2intro/1'>The SHOC2 subunit</scene> uses a crescent shape to enhance substrate interactions and complex stability.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952695/Pp1cintro/3'>The PP1C subunit</scene> contains the the catalytic site of the complex which dephosphorylates the N-terminal phosphoserine (NTpS) of RAF green link here.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952694/Pp1ccorrectintro/1'>The MRAS subunit</scene> binds to GTP which causes assembly of the SMP complex. The <scene name='95/952695/413cellmemprotrusion/4'>C-terminus of MRAS</scene> localizes the complex to the cell membrane.<ref name="Liau">PMID: 35768504</ref> Once the SMP compelx is assembled, MRAS can bind to <scene name='95/952695/Raf/3'>RAF</scene>, allowing the [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000522/. signaling cascade] to continue. Mutations in one or multiple of these subunits | <scene name='95/952695/Overall_image/2'>The SHOC2-MRAS-PP1C</scene> (SMP) holophosphatase complex functions as a key regulator of the [https://www.nature.com/scitable/topicpage/rtk-14050230/#:~:text=One%20of%20the%20most%20common,anchored%20to%20the%20plasma%20membrane. receptor tyrosine kinase (RTK)] signaling pathway by removing an inhibitory phosphate on the [https://www.sciencedirect.com/science/article/pii/S0167488907001164. RAF] family of proteins to allow for [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536342/. MAPK signaling].<ref name="Kwon">PMID: 35831509</ref> This interaction of the RTK-RAS pathway and the SMP complex drives cell proliferation.<ref name="Hauseman">PMID:35830882</ref> The SMP complex is made of three subunits, SHOC2, PP1C, and MRAS. Each of these subunits has a different shape that corresponds to its different function. <scene name='95/952695/Shoc2intro/1'>The SHOC2 subunit</scene> uses a crescent shape to enhance substrate interactions and complex stability.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952695/Pp1cintro/3'>The PP1C subunit</scene> contains the the catalytic site of the complex which dephosphorylates the N-terminal phosphoserine (NTpS) of RAF green link here.<ref name="Liau">PMID: 35768504</ref> <scene name='95/952694/Pp1ccorrectintro/1'>The MRAS subunit</scene> binds to GTP which causes assembly of the SMP complex. The <scene name='95/952695/413cellmemprotrusion/4'>C-terminus of MRAS</scene> localizes the complex to the cell membrane.<ref name="Liau">PMID: 35768504</ref> Once the SMP compelx is assembled, MRAS can bind to <scene name='95/952695/Raf/3'>RAF</scene>, allowing the [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000522/. signaling cascade] to continue. Mutations in one or multiple of these subunits can lead to over-activation of the signaling pathway, which may result in cancer and developmental disorders called [https://kidshealth.org/en/parents/rasopathies.html RASopathies].<ref name="Kwon">PMID: 35831509</ref> | ||
There are many regulatory mechanisms that serve as a lock on this [https://www.cancer.gov/research/key-initiatives/ras/about#:~:text=RAS%20proteins%20are%20important%20for,inactive%20(GDP%20form)%20states. RAS]-[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536342/. MAPK] pathway, decreasing the likelihood of unintentional pathway activation. <ref name="Hauseman">PMID:35830882</ref> One example is <scene name='95/952695/14-3-3/1'>14-3-3</scene>, a protein dimer that keeps inactive RAF localized to the cytoplasm. An N-terminal phosphorylated serine (NTpS) keeps RAF bound to this protein dimer, and when the SMP complex is assembled, the catalytic subunit, PP1C, removes the phosphate group from the serine residue, releasing RAF from <scene name='95/952695/14-3-3/1'>14-3-3</scene>, and activating the RAS-MAPK cell proliferation pathway. <ref name="Hauseman">PMID:35830882</ref> | There are many regulatory mechanisms that serve as a lock on this [https://www.cancer.gov/research/key-initiatives/ras/about#:~:text=RAS%20proteins%20are%20important%20for,inactive%20(GDP%20form)%20states. RAS]-[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536342/. MAPK] pathway, decreasing the likelihood of unintentional pathway activation. <ref name="Hauseman">PMID:35830882</ref> One example is <scene name='95/952695/14-3-3/1'>14-3-3</scene>, a protein dimer that keeps inactive RAF localized to the cytoplasm. An N-terminal phosphorylated serine (NTpS) keeps RAF bound to this protein dimer, and when the SMP complex is assembled, the catalytic subunit, PP1C, removes the phosphate group from the serine residue, releasing RAF from <scene name='95/952695/14-3-3/1'>14-3-3</scene>, and activating the RAS-MAPK cell proliferation pathway. <ref name="Hauseman">PMID:35830882</ref> | ||
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MRAS contains two regions called Switch I (SWI) and Switch II (SWII) that undergo conformational changes depending if MRAS is bound to GDP or GTP <ref name="Liau">PMID: 35768504</ref>. The conformation of these switches determines if the SMP complex can form or not. Mutations to MRAS lead to consistent GTP-loading, causing an increase in the formation of the SMP complex and there is consistent activation of the cell-proliferation pathway in the absence of external growth factors. | MRAS contains two regions called Switch I (SWI) and Switch II (SWII) that undergo conformational changes depending if MRAS is bound to GDP or GTP <ref name="Liau">PMID: 35768504</ref>. The conformation of these switches determines if the SMP complex can form or not. Mutations to MRAS can lead to consistent GTP-loading, causing an increase in the formation of the SMP complex and there is consistent activation of the cell-proliferation pathway in the absence of external growth factors. | ||