Figure 9.

Schematic diagram of the role of the Rheb/mTORC1/S6K1 and 4E-BP1 pathway in RGC survival and axon regeneration.

(A) S16H mutation in Rheb results in a constitutively GTP-bound Rheb as an activated form. Constitutively active Rheb stimulates mTORC1, which subsequently phosphorylates both S6K1 and 4E-BP1 and results in the promotion of protein synthesis. S6K1 is activated by phosphorylation, whereas 4E-BP1 is inhibited by phosphorylation. Both S6K1 activation and 4E-BP1 inhibition contribute to axon regeneration. Activated S6K1 also contributes to RGC survival and enlarged neural size. In contrast, 4E-BP1 inhibits axon regeneration but increases surviving RGCs. We speculate that unknown downstream effectors of mTORC1 also contribute to axon regeneration. (B) Constitutively active Rheb activates mTORC1, which in turn phosphorylates the two downstream effectors S6K1 and 4E-BP1. Phosphorylation of S6K1 supports RGC survival, whereas phosphorylation of 4E-BP1 plays a contrary role. However, S6K1 activation seems to be dominating in this context, and the impact of 4E-BP1 phosphorylation is masked and compensated by the positive effect of active S6K1. (C) Overexpression of non-phosphorylatable 4E-BP1 (4E-BP1-4A) protects RGCs independent of mTORC1 activity. Thus, inactivation of endogenous 4E-BP1 upon caRheb becomes irrelevant, and 4E-BP1-4A compensates for the low level of endogenous 4E-BP1 activity and further promotes RGC survival under these conditions. 4E-BP1: mTORC1 downstream effector; caRheb: constitutively active Rheb; GTP: guanosine triphosphate; mTORC1: mammalian target of rapamycin complex 1; RGC: retinal ganglion cell; Rheb: Ras homolog enriched in brain; S6K1: mTORC1 downstream effector; WT: wild type.