PRP4 kinase induces actin rearrangement and epithelial-mesenchymal transition through modulation of the actin-binding protein cofilin

• Published in: Experimental cell research Vol. 369; no. 1; pp. 158 - 165
• Main Authors: Islam, Salman Ul, Ahmed, Muhammad Bilal, Lee, Su Jin, Shehzad, Adeeb, Sonn, Jong Kyung, Kwon, Oh-Shin, Lee, Young Sup
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2018
• Subjects: 60 APPLIED LIFE SCIENCES; ACTIN; Actin cytoskeleton; Cofilin; EMT; HUMAN POPULATIONS; LARGE INTESTINE; MESSENGER-RNA; MICROTUBULES; NEOPLASMS; PHOSPHATASES; PHOSPHOTRANSFERASES; Pre-mRNA processing factor 4B (PRP4); Protein Phosphatase 1A (PP1A); Pre-mRNA processing factor 4B (PRP4); Cofilin; Actin cytoskeleton; EMT; Protein Phosphatase 1A (PP1A)
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2018.05.018

Cell actin cytoskeleton is primarily modulated by Rho family proteins. RhoA regulates several downstream targets, including Rho-associated protein kinase (ROCK), LIM-Kinase (LIMK), and cofilin. Pre-mRNA processing factor 4B (PRP4) modulates the actin cytoskeleton of cancer cells via RhoA activity inhibition. In this study, we discovered that PRP4 over-expression in HCT116 colon cancer cells induces cofilin dephosphorylation by inhibiting the Rho-ROCK-LIMK-cofilin pathway. Two-dimensional gel electrophoresis, and matrix-assisted laser desorption/ionization time-of-flight mass-spectrometry (MALDI-TOF MS) analysis indicated increased expression of protein phosphatase 1A (PP1A) in PRP4-transfected HCT116 cells. The presence of PRP4 increased the expression of PP1A both at the mRNA and protein levels, which possibly activated cofilin through dephosphorylation and subsequently modulated the cell actin cytoskeleton. Furthermore, we found that PRP4 over-expression did not induce cofilin dephosphorylation in the presence of okadaic acid, a potent phosphatase inhibitor. Moreover, we discovered that PRP4 over-expression in HCT116 cells induced dephosphorylation of migration and invasion inhibitory protein (MIIP), and down-regulation of E-cadherin protein levels, which were further restored by the presence of okadaic acid. These findings indicate a possible molecular mechanism of PRP4-induced actin cytoskeleton remodeling and epithelial-mesenchymal transition, and make PRP4 an important target in colon cancer. Proposed model for PRP4-induced cofilin and MIIP dephosphorylation and epithelial-mesenchymal transition (EMT) induction. PRP4 over-expression results in cofilin and MIIP dephosphorylation, causing actin dynamics to increase, which may lead to EMT. Another proposed pathway for EMT induction by dephosphorylated MIIP is illustrated in the black-dotted panel. MIIP may inhibit the Rac1 signaling pathway through PAK1 (Rac1 downstream target) binding competition, which results in reduced lamellipodia formation and, finally, EMT. [Display omitted] •PRP4 is involved in pre-mRNA splicing and cell signalling.•PRP4 modulates the actin cytoskeleton of cancer cells via RhoA activity inhibition.•PRP4 induces cofilin dephosphorylation by inhibiting the Rho-ROCK-LIMK-cofilin pathway in HCT116 cells.•Dephosphorylation of cofilin results in F-actin stabilization, re-distribution of cytoplasmic actin, formation of actin stress fibers, and inhibition of cell motility.•PRP4 over-expression induces the expressions of PP1A, which directly or indirectly dephosphorylates cofilin, resulting in actin cytoskeleton rearrangement, downregulation of E-cadherin, and EMT induction. Cofilin activation may be associated with EMT properties, and promotes the progression of human colon cancer.