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. Author manuscript; available in PMC: 2021 Nov 1.
Published in final edited form as: Semin Cancer Biol. 2019 Dec 12;66:116–128. doi: 10.1016/j.semcancer.2019.11.007

Figure 3: ER translocation of MAPK pathways and autophagy.

Figure 3:

During targeted therapy with BRAF and MEK inhibition in BRAF mutant melanoma, a cytoplasmic pool of Grp78 binds to the scaffold protein KSR2 which recruits NRAS, BRAF, MEK and ERK. This multiprotein complex is shuttled to Rab5+ on early endosomes on ER membrane. MAPK components translocate to ER via the ER translocase SEC61. ERK translocates from ER back to the cytoplasm where ERK is phosphorylated by the cytoplasmic domain of PERK and ERK is reactivated. This reactivated ERK promotes phosphorylation of ATF4 independent of eIF2α and the UPR. ATF4 activates autophagy through transcriptional upregulation of multiple autophagy genes.