Coordination of cell growth and division by the ubiquitin-proteasome system

Abstract

The coupling of cellular growth and division is crucial for a cell to make an accurate copy of itself. Regulated protein degradation by the ubiquitin-proteasome system (UPS) plays an important role in the coordination of these two processes. Many ubiquitin ligases, in particular the Skp1-Cullin-F-box (SCF) family and the Anaphase-Promoting Complex (APC), couple growth and division by targeting cell cycle and metabolic regulators for degradation. However, many regulatory proteins are targeted by multiple ubiquitin ligases. As a result, we are only just beginning to understand the complexities of the proteolytic regulatory network that connects cell growth and the cell cycle.

Figure 1. The E3 network that ubiquitylatesG1 and G1/S cyclins and CKIs

Diagram of G1 and G1/S phase cyclins and CKIs, and the E3s that have been implicated in their degradation. Yeast proteins are diagramed in the top half of the figure, vertebrate proteins are diagrammed in the bottom half. SCF ligases are indicated by their, specific FBPs. Related FBPs are colored similarly (yeast Cdc4 and vertebrate Fbw7 in red, yeast Grr1 and vertebrate Skp2 in blue).

Figure 2. Glycolysis is downregulated through the targeting of 6-phosphofructo-2-kinase by the UPS

One rate-limiting step of glycolysis is the conversion of fructose-6-phosphate (F-6-P) to fructose-1,6-bisphosphate (F-1,6-BP), which is catalyzed by phosphofructokinase (PFK1). The 6-phosphofructo-2-kinase enzymes (Pfk27 in yeast and PFKFB3 in mammals) generate the second messenger fructose-2,6-bisphosphate (F-2,6-BP) which is an essential activator of PFK1. By degrading these enzymes that generate F-2,6-BP, the UPS can downregulate glycolysis in response to specific cues. (A) In yeast, low extracellular glucose promotes the ubiquitin-mediated degradation of Pfk27 by SCF^Grr1. (B) In mammals, glycolysis is restricted to S phase through the combination of cell cycle-regulated transcription and degradation of PFKFB3 in G1 by APC^Cdh1 and in S phase by SCF^βTRCP.