The Skp2-SCF E3 Ligase Regulates Akt Ubiquitination, Glycolysis, Herceptin Sensitivity, and Tumorigenesis

Abstract

Akt kinase plays a central role in cell growth, metabolism and tumorigenesis. Although TRAF6 E3 ligase orchestrates IGF-1-mediated Akt ubiquitination and activation, it is unclear whether TRAF6 is involved in Akt activation by other growth factor receptors as well. Here we show that Akt ubiquitination is also induced by activation of ErbB receptors; unexpectedly, Skp2 SCF complex, but not TRAF6, is a critical E3 ligase for ErbB receptor-mediated Akt ubiquitination and membrane recruitment. Interestingly, Skp2 deficiency impairs Akt activation, Glut1 expression, glucose uptake and glycolysis, and breast cancer progression in various tumor models. Moreover, Skp2 overexpression correlates with Akt activation, breast cancer metastasis, and serves as a marker for poor prognosis in Her2-positive patients. Finally, we showed that Skp2 silencing sensitizes Her2-overexpressing tumors to Herceptin treatment. Our study suggests that distinct E3 ligases are utilized by diverse growth factors for Akt ubiquitination and activation.

Skp2 is required for Aurora B activation in cell mitosis and spindle checkpoint

“…[4][5][6] As well as the critical role in cell-cycle progression, Skp2 also displays oncogenic activity. 4,5,7 Furthermore, our recent study revealed that Skp2 also played an important role in DNA Damage response (DDR) by regulating ATM kinase and Homologous Recombination (HR) repair. 8 As the 2 main monitoring machineries, lots of evidence indicates that there exists crosstalk between mitosis regulation and DNA repair machinery.…”

Akt: a new activation mechanism

“…Another possibility is that pS477/T479 happens after Akt membrane recruitment, and simply increases the binding affinity between Akt and PDK1, similar to its effect on pS473 and mTORC2. Finally, ubiquitination of Akt on the PH domain by E3 ligases upon growth factor stimulations translocates Akt to the plasma membrane for activation and downstream biological functions such as glycolysis and tumorigenesis [7,8]. It will also be interesting to see the crosstalk between these two important Akt modification events.…”

The role of K63‐linked polyubiquitination in cardiac hypertrophy

“…This study also indicated that ubiquitination‐mediated AKT membrane recruitment does not result from PIP3 binding 80. Apart from this, K14 residue within the PIP3‐binding domain of AKT is required for its with PIP3, which is evident from the inability of binding of mutant (K14R) AKT with PIP3 77, 81, 82. The expression of TRAF2, an E3 ligase, is up‐regulated in the failing heart and its overexpression enhances cardiac hypertrophy and ventricular dysfunction by activating AKT/GSK3β signalling 83…”