Sandbox Reserved 1790: Difference between revisions

The SMP signaling pathway begins with the formation of the SMP complex. Initially, a ligand must bind to a receptor tyrosine kinase. This signals SHOC2 to bind to PP1C forming a binary complex that then binds to the membrane bound MRAS. There is some discrepancy about when the different proteins of the SMP complex come together <ref name="Liau">PMID:35768504</ref>.  Some experiments indicate that the three proteins bind at the same time but the order is largely unknown. Once the SMP complex forms, its intracellular target is a key inactivation phosphorylation (Ser259) on MAPK Raf1. The serine is directly dephosphorylated by PP1C, while SHOC2 and MRAS increase PP1C’s specificity for S259 on Raf <ref name="Liau" />. When analyzing the surface structure of SHOC1-PP1C-MRAS, there was a hydrophobic groove on the SHOC2 terminus and another hydrophobic groove near the active site on PP1C <ref name="Liau" />. This region is crucial in making PP1C specific to Raf, because the NTpS region that is right next to the phosphoserine on Raf is able to bind to the hydrophobic patch on both SHOC2 and PP1C <ref name="Liau" />.  

Mutations affecting SMP complex formation and stability can increase or decrease MAPK signaling, where increased stability of the complex increases MAPK signaling while decreased stability decreases signaling <ref name="Liau" />. There are a set of mutations that can happen on the SMP complex as a whole that can cause [https://www.mayoclinic.org/diseases-conditions/noonan-syndrome/symptoms-causes/syc-20354422. Noonan syndrome], a rasopathy disorder <ref name="Liau" />. On SHOC2, if the following mutations S2G, C260Y, and P510L caused differences in the complex formation with PP1C <ref name="Liau" />. On PP1C, the mutation P50R resulted in stronger ionic interactions with residues on SHOC2, resulting in a more stabilized complex <ref name="Liau" />. On MRAS, mutations such as G23V and T681I, can increase the proportion of MRAS that is GTP bound, which results in increased affinity in the SMP complex overall <ref name="Liau" />. If these mutations happen all at once, or just one or two at a time, it can still significantly alter the functionality of the SMP complex <ref name="Liau" />. This can lead to diseases like Noonan syndrome, which is where there are developmental and growth issues, and can even lead to cancers <ref name="Liau" />.