Cables1 Complex Couples Survival Signaling to the Cell Death Machinery

Abstract

Cables1 is a candidate tumor suppressor that negatively regulates cell growth by inhibiting cyclin-dependent kinases. Cables1 expression is lost frequently in human cancer but little is known about its regulation. Here we report that Cables1 levels are controlled by a phosphorylation and 14-3-3 dependent mechanism. Mutagenic analyses identified two residues, T44 and T150, that are specifically critical for 14-3-3 binding and that serve as substrates for phosphorylation by the cell survival kinase Akt, which by binding directly to Cables1 recruits 14-3-3 to the complex. In cells Cables1 overexpression induced apoptosis and inhibited cell growth in part by stabilizing p21 and decreasing Cdk2 kinase activity. Ectopic expression of activated Akt prevented Cables1-induced apoptosis. Clinically, levels of phosphorylated Cables1 and phosphorylated Akt correlated with each other in human lung cancer specimens, consistent with pathophysiologic significance. Together, our results illuminated a dynamic regulatory system through which activated Akt and 14-3-3 work directly together to neutralize a potent tumor suppressor function of Cables1.

The Emerging Role of Cables1 in Cancer and Other Diseases

“…Our data show that Cables1 competes with PSMA3 to bind p21, and protects p21 from PSMA3mediated proteasomal degradation; the expression level of Cables1 is correlated with that of p21 in human lung cancer tissues (Shi et al, 2015a). Additionally, we found a phosphorylation-dependent and 14-3-3-mediated mechanism that regulates the tumor suppressor function of Cables1 (Shi et al, 2015b). Akt directly interacts with and phosphorylates Cables1 to recruit 14-3-3 to the complex; activated Akt is able to prevent cell apoptosis induced by Cables1 (Shi et al, 2015b).…”

“…Additionally, we found a phosphorylation-dependent and 14-3-3-mediated mechanism that regulates the tumor suppressor function of Cables1 (Shi et al, 2015b). Akt directly interacts with and phosphorylates Cables1 to recruit 14-3-3 to the complex; activated Akt is able to prevent cell apoptosis induced by Cables1 (Shi et al, 2015b).…”

“…2A) (Yamochi et al, 2001b). Akt also phosphorylates Cables1 at T309 and T415 sites to recruit 14-3-3 binding (Shi et al, 2015b).…”

“…Recently, our work revealed a novel tumor suppressor function of Cables1 in antagonizing proteasome subunit alpha type 3 (PSMA3) to increase the stability of cell cycle regulator p21 proteins (Shi et al, 2015a). In addition, we elucidated a dynamic regulatory system in which activated Akt can phosphorylate Cables1 and recruit 14-3-3 to neutralize the tumor suppressor function of Cables1, suggesting that the Akt/Cables1 interface may represent a novel anticancer target for potential therapeutic interventions (Shi et al, 2015b). As shown in the timeline of Cables1 research (Fig.…”

Atypical cyclins: the extended family portrait

“…Indeed, later studies demonstrated that loss of CABLES1 enhanced tumor progression in the Apc(Min/+) mouse model, which may be a consequence of increased activation of the Wnt/β-catenin pathway [40]. It was also shown that CABLES1 overexpression induced apoptosis and inhibited cell growth at least in part through p21 stabilization [41,42], further consolidating that CABLES1 acts as a tumor suppressor. Moreover, CABLES1…”