Regulation of phosphoglucomutase 1 phosphorylation and activity by a signaling kinase

Abstract

We have identified a novel mechanism of cross-talk between cell signaling and metabolic pathways, whereby the signaling kinase p21-activated kinase 1 (Pak1) binds to, phosphorylates and enhances the enzymatic activity of phosphoglucomutase 1 (PGM), an important regulatory enzyme in cellular glucose utilization and energy homeostasis. Pak1 and PGM were colocalized in model cell systems and showed functional interactions in a physiological setting. Strong direct interaction of PGM with Pak1 but not Pak2, Pak3, or Pak4 was observed. PGM binding was within 75-149 amino acids (aa) of Pak1, while Pak1 binding to PGM was in the N-terminal 96 aa. Pak1-mediated phosphorylation of PGM selectively on threonine 466 significantly increased PGM enzymatic activity and could be blocked by transfection with a dominantnegative Pak1 expression vector and by Pak1-specific small inhibitory RNA. Stable transfection of PGM into PGM-deficient K-562 leukemia cells further demonstrated the role of Pak1 in regulating PGM activity. The results presented here provide new evidence that the cell signaling kinase Pak1 is a novel regulator of glucose metabolism through its phosphorylation and regulation of PGM activity. These findings suggest a new mechanism whereby growth factor signaling may coordinately integrate metabolic regulation with established signaling functions of cell cycle regulation and cell growth.

Apoptosis in muscle-to-meat aging process: The omic witness

“…It is one of the three enzymes (glycogen phosphorylase; debranching enzyme; PGM) whose sequential action leads to the release of a glucose-6-phosphate monomer from glycogen. Literature reports the enhancing effect of phosphorylation on PGM activity [50], and the Western results follow the expectations: muscle cells subjected to the anoxic conditions become needy of the lacking ATP no more produced by Krebs cycle and oxidative phosphorylation, so they veer to an anaerobic ATP production by increasing the degree of glycolysis, exploiting glycogen reservoirs and extracting glucose-6-phosphate monomers for directing them to glycolytic consumption. Heat shock protein, alpha-crystallin-related, B6 aValues between brackets indicate statistically significant peptides (p < 0.05).…”

Nuclear Localization and Chromatin Targets of p21-activated Kinase 1

“…The noted Pak1-mediated EGF-induced enhancement of the key rate-limiting glycolytic enzyme PFK might participate in the enhancing glycolysis. In this context, recently Pak1 has also been shown to phosphorylate and stimulate phospho-glucomutase activity, and thus, may be involved in shifting the metabolism toward more glycolysis and the pentose phosphate pathway (27). In addition to this, by demonstrating that Pak1 associates with and enhances the expression of PFK-M, we have highlighted one of the possible modes by which increased growth factor signaling and deregulated Pak1 activity might cooperate in altering the cellular metabolism and potentially aid in the manifestation of the cancerous phenotype in cells.…”

Dynein Light Chain 1 Contributes to Cell Cycle Progression by Increasing Cyclin-Dependent Kinase 2 Activity in Estrogen-Stimulated Cells

“…The pGEX-KG vector was generously provided by Bernard Ducommun (Universite P. Sabatier, Toulouse, France), and the cytomegalovirus-Cdk2 vector was kindly provided by Jian Kuang (The University of Texas M. D. Anderson Cancer Center, Houston, TX). pGEX-Pak1 and pGEX-PGM were used previously in our laboratory (12). Stable cell lines expressing T7-DLC1 were described previously (7).…”