This entry represents eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1). EIF4EBP1 is a repressor of translation that binds to EIF4E and prevents its assembly into the eIF4F complex. EIF4EBP1 has to be hypophosphorylated to bind to EIF4E; the hyperphosphorylated form dissociates from EIF4E []. The phosphorylation state of EIF4EBP1 is affected by hormones such as insulin []and is regulated by mTORC1 []. When eIF4E levels are low, hypophosphorylated EIF4EBP1 is ubiquitinated by the BCR(KLHL25) complex, leading to its degradation, and translation is maintained [].
Rheb is a Ras-like small GTPase essential for TORC1 activity in mammals []. Rheb activates the protein kinase activity of mTORC1 (rapamycin), and in turn stimulates the phosphorylation of S6K1 and EIF4EBP1 through activation of mTORC1 signaling [, , ]. Rheb alternates between an inactive form bound to GDP and an active form bound to GTP. It is inactivated by TSC1-TSC2 via the GTPase activating protein (GAP) domain of TSC2 []. The mechanism of action of Rheb has been determined from the tertiary structure [].
The activity of GTPases is regulated by the opposing effects of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Tuberin (tuberous sclerosis 2 protein or Tsc2) is believed to be a tumor suppressor and is able to stimulate specific GTPases. It stimulates the intrinsic GTPase activity of the Ras-related protein Rap1A and Rab5 [, ]. In complex with Tsc1, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling. It acts as a GTPase-activating protein (GAP) for the small GTPase RheB, a direct activator of the protein kinase activity of mTORC1 [, ]. Ral GTPase-activating protein subunit alpha is the catalytic subunit of the heterodimeric RalGAP complex which acts as a GTPase activator for the Ras-like small GTPases RalA and RalB []. RalGAP complexes share structural and catalytic similarities with the tuberous sclerosis tumor suppressor complex [].
