GP78 Cooperates with Dual-Specificity Phosphatase 1 To Stimulate Epidermal Growth Factor Receptor-Mediated Extracellular Signal-Regulated Kinase Signaling.

Abstract

GP78 is an autocrine motility factor (AMF) receptor (AMFR) with E3 ubiquitin ligase activity that plays a significant role in tumor cell proliferation, motility, and metastasis. Aberrant extracellular signal-regulated kinase (ERK) activation via receptor tyrosine kinases promotes tumor proliferation and invasion. The activation of GP78 leads to ERK activation, but its underlying mechanism is not fully understood. Here, we show that GP78 is required for epidermal growth factor receptor (EGFR)-mediated ERK activation. On one hand, GP78 interacts with and promotes the ubiquitination and subsequent degradation of dual-specificity phosphatase 1 (DUSP1), an endogenous negative regulator of mitogen-activated protein kinases (MAPKs), resulting in ERK activation. On the other hand, GP78 maintains the activation status of EGFR, as evidenced by the fact that EGF fails to induce EGFR phosphorylation in GP78-deficient cells. By the regulation of both EGFR and ERK activation, GP78 promotes cell proliferation, motility, and invasion. Therefore, this study identifies a previously unknown signaling pathway by which GP78 stimulates ERK activation via DUSP1 degradation to mediate EGFR-dependent cancer cell proliferation and invasion.

• Authors: Dhong Hyo Kho, Mohammed Hafiz Uddin, Madhumita Chatterjee, Andreas Vogt, Avraham Raz, Gen Sheng Wu
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 39 Issue 11 (06 01 2019) ISSN: 1098-5549 [Electronic] United States
• PMID: 31061093 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2019 American Society for Microbiology.

Chemical References

• Epidermal Growth Factor
• AMFR protein, human
• Receptors, Autocrine Motility Factor
• EGFR protein, human
• ErbB Receptors
• DUSP1 protein, human
• Dual Specificity Phosphatase 1

Topics

• Carcinoma, Hepatocellular (metabolism)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Dual Specificity Phosphatase 1 (chemistry, metabolism)
• Epidermal Growth Factor (metabolism)
• ErbB Receptors (metabolism)
• HEK293 Cells
• Humans
• Liver Neoplasms (metabolism)
• MAP Kinase Signaling System
• Neoplasm Invasiveness
• Phosphorylation
• Proteolysis
• Receptors, Autocrine Motility Factor (metabolism)
• Ubiquitination