Tuberin: A Stimulus-Regulated Tumor Suppressor Protein Controlled by a Diverse Array of Receptor Tyrosine Kinases and G Protein-Coupled Receptors

Abstract

Tuberin, a tumor suppressor protein, is involved in various cellular functions including survival, proliferation, and growth. It has emerged as an important effector regulated by receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). Regulation of tuberin by RTKs and GPCRs is highly complex and dependent on the type of receptors and their associated signaling molecules. Apart from Akt, the first kinase recognized to phosphorylate and inactivate tuberin upon growth factor stimulation, an increasing number of kinases upstream of tuberin have been identified. Furthermore, recruitment of different scaffolding adaptor components to the activated receptors appears to play an important role in the regulation of tuberin activity. More recently, the differential regulation of tuberin by various G protein family members have also been intensively studied, it appears that G proteins can both facilitate (e.g., G_i/o) as well as inhibit (e.g., G_q) tuberin phosphorylation. In the present review, we attempt to summarize our emerging understandings of the roles of RTKs, GPCRs, and their cross-talk on the regulation of tuberin.

The Rheb–mTOR Pathway Is Upregulated in Reactive Astrocytes of the Injured Spinal Cord

“…For example, the Erk1/Erk2 MAP kinases and their downstream target p90 Rsk can phosphorylate Tuberin and inhibit its activity, leading to downstream Rheb and mTORC1 activation (Bhaskar and Hay, 2007; Wu et al, 2007). EGF treatment promoted phosphorylation and activation of Erk1/Erk2 in cultured astrocytes (Fig.…”

“…3), which is one of the sites involved in Akt activation (Bhaskar and Hay, 2007; Chiang and Abraham, 2007). Akt in turn can activate mTORC1 by phosphorylating Tuberin at serine 939 and threonine 1462, leading to its inactivation (Wu et al, 2007). Tuberin T1462 phosphorylation was indeed increased following EGF stimulation and the PI3 kinase inhibitor, LY294002, abolished not only Akt but also Tuberin phosphorylation, suggesting that Tuberin phosphorylation occurs downstream of PI3 kinase and Akt (Fig.…”

Multiple Gi Proteins Participate in Nerve Growth Factor-Induced Activation of c-Jun N-terminal Kinases in PC12 Cells

“…It is noteworthy that b-arrestin 2 has been identified as a binding partner with JNK3 and acts as a receptor-regulated MAPK scaffold for JNK activation under the control of a GPCR [71]. Furthermore, there is increasing evidence for the convergence of signals from RTKs and GPCRs along with the recruitment of scaffolding adaptor proteins that can channel various extracellular stimuli to the phosphorylation of tuberin via the PI3K/Akt pathway [72][73][74]. Particular to NGF, TrkA can be coupled with the PI3K adaptor protein Grb2, the phosphorylation of which is in turn linked to a G i -coupled receptor [72].…”

“…Furthermore, there is increasing evidence for the convergence of signals from RTKs and GPCRs along with the recruitment of scaffolding adaptor proteins that can channel various extracellular stimuli to the phosphorylation of tuberin via the PI3K/Akt pathway [72][73][74]. Particular to NGF, TrkA can be coupled with the PI3K adaptor protein Grb2, the phosphorylation of which is in turn linked to a G i -coupled receptor [72]. Even though these findings do not provide obvious linkages between the TrkA receptor and G i/o proteins, they strengthen the possibility that G proteins do indeed participate in mediating NGF-induced signals.…”

Regulation of mTOR and p70 S6 kinase by the muscarinic M4 receptor in PC12 cells

“…Receptor tyrosine kinases (RTKs) such as the TrkA receptors can also stimulate the PI3K/Akt/tuberin pathway efficiently (Wu and Wong, 2005b, c, 2006; Wu et al., 2006). Yet, unlike the transient signals arising from GPCRs, RTK‐induced phosphorylations of Akt and tuberin are relatively sustained (Wu and Wong, 2005a, b, c; Wu and Wong, 2006).…”