PAK4 kinase-mediated SCG10 phosphorylation involved in gastric cancer metastasis.

Abstract

Superior cervical ganglia 10 (SCG10), as a microtubule (MT) destabilizer, maintains MT homeostasis and has a critical role in neuronal development, but its function in tumorigenesis has not been characterized. In the present study, we demonstrated that p21-activated kinase 4 (PAK4)-mediated SCG10 phosphorylation regulates MT homeostasis in metastatic gastric cancer. Our results indicate that SCG10 is a physiological substrate of PAK4, which is phosphorylated on serine 50 (Ser50) in a PAK4-dependent manner. Phosphorylated SCG10 regulated MT dynamics to promote gastric cancer cell migration and invasion in vitro and metastasis in a xenograft mouse models. Inhibiting PAK4, either by LCH-7749944 or RNA interference, resulted in the inhibition of Ser50 phosphorylation and a blockade to cell invasion, suggesting that PAK4-SCG10 signaling occurs in gastric cancer cell invasion. Moreover, we demonstrated a strong positive correlation between PAK4 and phospho-Ser50 SCG10 expression in gastric cancer samples. We also showed that high expression of SCG10 phospho-Ser50 is highly correlated to an aggressive phenotype of clinical gastric cancer. These findings revealed a novel function of SCG10 in promoting invasive potential of gastric cancer cells, suggesting that blocking PAK4-mediated SCG10 phosphorylation might be a potential therapeutic strategy for metastasis of gastric cancer.

• Authors: Q Guo, N Su, J Zhang, X Li, Z Miao, G Wang, M Cheng, H Xu, L Cao, F Li
• Journal: Oncogene (Oncogene) Vol. 33 Issue 25 Pg. 3277-87 (Jun 19 2014) ISSN: 1476-5594 [Electronic] England
• PMID: 23893240 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HGF protein, human
• Membrane Proteins
• STMN2 protein, human
• Stathmin
• Serine
• Hepatocyte Growth Factor
• PAK4 protein, human
• p21-Activated Kinases
• cdc42 GTP-Binding Protein

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• Cell Movement (physiology)
• Female
• HEK293 Cells
• Hepatocyte Growth Factor (metabolism)
• Heterografts
• Humans
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Microtubules (metabolism, pathology)
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Transplantation
• Phosphorylation
• Serine (metabolism)
• Stathmin
• Stomach Neoplasms (enzymology, metabolism, pathology)
• cdc42 GTP-Binding Protein (metabolism)
• p21-Activated Kinases (metabolism)