Oncogenic PAK4 regulates Smad2/3 axis involving gastric tumorigenesis

Abstract

The alteration of p21-activated kinase 4 (PAK4) and transforming growth factor-beta (TGF-β) signaling effector Smad2/3 was detected in several types of tumors, which acts as oncogenic factor and tumor suppressor, but the relationship between these events has not been explored. Here, we demonstrate that PAK4 interacts with and modulates phosphorylation of Smad2/3 via both kinase-dependent and kinase-independent mechanisms, which attenuate Smad2/3 axis transactivation and TGF-β-mediated growth inhibition in gastric cancer cells. First, PAK4 interaction with Smad2/3, which is independent of PAK4 kinase activity, blocks TGF-β1-induced phosphorylation of Smad2 Ser465/467 or Smad3 Ser423/425 and the consequent activation. In addition, PAK4 phosphorylates Smad2 on Ser465, leading to the degradation of Smad2 through ubiquitin-proteasome-dependent pathway under hepatocyte growth factor (HGF) stimulation. Interestingly, PAK4 expression correlates negatively with phospho-Ser465/467 Smad2 but positively with phospho-Ser465 Smad2 in gastric cancer tissues. Furthermore, the expressions of HGF, phospho-Ser474 PAK4 and phospho-Ser465 Smad2 are markedly increased in gastric cancer tissues, and the expression of Smad2 is decreased in gastric cancer tissues. Our results document an oncogenic role of PAK4 in repression of Smad2/3 transactivation that involved in tumorigenesis, and suggest PAK4 as a potential therapeutic target for gastric cancer.

Tracing PAKs from GI inflammation to cancer

“…TGF-β transmits signals to the nucleus via a network of multiprotein complexes using the SMA and mothers against decapentaplegic (MAD; SMAD) family of proteins. Loss of SMAD was correlated to GC susceptibility,140 and HGF activation of PAK4 induced SMAD2 phosphorylation and proteasomal degradation 17. One mechanism in which PAK4 may promote GC metastasis is through the modification of microtubule homeostasis proteins such as superior cervical ganglia 10 (SCG10).…”

“…Overall, PAK1 and PAK4 are the most investigated of all PAKs, and have been brought into focus due to their association with various malignancies 1. PAK overexpression contributes to tumour invasiveness in uveal melanoma,7 8 neurofibromatosis,9 breast,10 11 cervical,12 colon,13 14 oesophageal,15 gastric,16 17 hepatic,18 lung,19 ovarian,20 prostate21 22 and thyroid cancer 23. PAKs were also correlated to inflammatory diseases such as rheumatoid arthritis24 and asthma 25.…”

Prognostic significance of PAK4 expression in gastric cancer

“…PAK4 expression in human samples or cell lines of gastric cancer has been investigated in other studies 15 17 18. These studies pointed to an underlying oncogenic potential of PAK4.…”

“…Cancer cells that have high PAK4 levels also have mutations in genes in the senescence pathway, such as p53, thus allowing them to undergo transformation rather than senescence 19. PAK4 interacts with Smad2/3 and phosphorylates Smad2/3, thereby impairing the transforming growth factor β1 (TGF-β1) signalling pathway, resulting in escape from TGF-β-mediated growth inhibition in gastric cancer cells 18. DiGeorge critical region 6 (DGCR6L), which may be involved in cancer cell migration and is necessary for PAK4 forming a complex with β-actin, interacts directly with PAK4 and enhances PAK4-mediated migration of human gastric cancer cells through LIMK1 17…”

Activated Pak4 expression correlates with poor prognosis in human gastric cancer patients

“…Overexpression of Pak4 was detected in GC as well as several other tumors [11][12][13][14][15]. Recent studies have demonstrated that Pak4 activity promotes cell migration and invasion in GC cell line SGC-7901 through HGF/Pak4/LIMK1/cofilin and MEK/MMP2 pathways [16].…”