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| == Introduction == | | == Introduction == |
| <scene name='95/952694/Overall_image/2'>The SHOC2-MRAS-PP1C</scene> (SMP) is a 3-subunit complex essential for cell proliferation and the survival of many cancers<ref name="Hauseman">PMID:35830882</ref> and RASopathies.<ref name="Kwon">PMID: 35831509</ref> The SMP holophosphatase complex functions as a key regulator of the receptor tyrosine kinase (RTK) signaling pathway by removing an inhibitory phosphate on the RAF family of proteins to allow for 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='95/952694/Shoc2intro/1'>The SHOC2 subunit</scene> uses a crescent shape to enhance substrate interactions and complex stability.<ref name="Liau">PMID: 35768504</ref> PP1C is a phosphatase, and this subunit contains 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 triggers assembly of the SMP complex. The C-terminus of the MRAS subunit localizes the complex to the cell membrane.<ref name="Liau">PMID: 35768504</ref> Mutations in one or multiple of these subunits leads to over-activation of the signaling pathway, which may result in cancer and developmental disorders called RASopathies.<ref name="Kwon">PMID: 35831509</ref>
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| There are many regulatory mechanisms that serve as a lock on this RAS-MAPK pathway, decreasing the likelihood of unintentional pathway activation. One is a protein dimer called 14-3-3 that keeps inactive RAF localized to the cytoplasm. An N-terminal phosphorylated serine 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, releasing RAF from the 14-3-3 dimer, and activating the RAS-MAPK cell proliferation pathway.
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| In all images and animations, {{Font color|cyan|SHOC2}} will be shown as cyan blue, {{Font color|lime|MRAS}} as lime, and {{Font color|violet|PP1C}} as violet. Other important components involved in the function of the SMP complex include the {{Font color|salmon|14-3-3}} dimer and {{Font color|slate-blue|Raf}}, which will be shown in salmon and slate-blue, respectively.
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| == Significance ==
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| === Cell Proliferation ===
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| The Ras-Raf signaling cascade as a whole is fundamental for cell growth and survival. When a membrane bound GTPase is activated by extracellular growth proteins, it binds to a GTP molecule which then activates Raf and the signaling cascade. However, Raf is typically kept in an auto-inhibited form. When MRAS is GTP-bound rather than GDP-bound, it triggers the formation of the SMP complex. The active site of PP1C, when in complex, is responsible for removing the residue that causes steric clash, and therefore, auto-inhibition. Extracellular growth factors trigger both formation of the SMP complex and Ras-Raf interaction through the binding of GTP to a Ras-protein, however, the SMP complex must remove the auto-inhibition before Ras and Raf can interact. Since SHOC2-PP1C-MRAS plays such a crucial role in the activation of the signaling cascade, many scientists say that cell proliferation is regulated by the SMP complex rather than the Ras-Raf interaction.
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