Table 1 The functions and regulation of the Cullin family in PI3K/AKT-mediated glucose metabolism.

From: RING-finger E3 ligases regulatory network in PI3K/AKT-mediated glucose metabolism

E3 ligases

Mechanisms

Biological response

References

CRL1

Skp2 deficiency impairs PI3K/AKT activation, GLUT1 expression, glucose uptake, and glycolysis. Skp2 can also ubiquitinate and promote the degradation of FOXO1.

Downregulation of the PI3K/AKT-GSK3β-FBW7 signaling axis promotes the destabilization of c-Myc, which inhibit expression of hexokinase 2.

PI3K/AKT↑

Glycolysis↑

Gluconeogenesis↓

[35]

[39,40,41]

[42,43,44,45,46,47,48,49,50]

CRL2

CRL2 pVHL plays a critical role in the control of HIF1α degradation. HIF1α induces the expression of GLUT1 and nearly all glycolysis enzymes.

The Cul2-Rbx1-SOCS complex ubiquitinates IRS1 and suppresses the activation of PI3K/AKT, which causes glucose metabolism changes.

Glycolysis↓

PI3K/AKT↓

Glycolysis↓

[21, 51,52,53,54,55,56,57,58,59,60]

[61, 62]

CRL4

COP1, part of the Cul4A-RING E3 ubiquitin ligase complex, plays an important role in the homeostasis of glucose. It reduces PTP1B activity and suppresses the expression of gluconeogenic genes.

PI3K/AKT↑

Glycolysis↑

Gluconeogenesis↓

[37],

[66,67,68,69,70,71]

CRL7

The SCF-Fbxw8 E3 ligase targets IRS-1 for degradation.

PI3K/AKT↓

Glycolysis↓

[29],

[72,73,74,75,76,77]

  1. CRLs cullin-RING ligase complexes, Skp2 S phase kinase-associated protein-2, PI3K phosphatidylinositol 3-kinase, GLUT1 glucose transporter 1, FOXO1 forkhead box O 1; FBW7 F-box and WD-repeat-domain-containing protein 7, HIF1α hypoxia-inducible factor 1α, Rbx1 RING box protein 1, SOCS suppressors of cytokine signaling, IRS1 insulin receptor substrate 1, COP1 constitutive photomorphogenesis protein 1, PTP1B protein-tyrosine phosphatase 1B.
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