☆ 4.6 Article

Novel participation of transglutaminase-2 through c-Jun N-terminal kinase activation in sphingosylphosphorylcholine-induced keratin reorganization of PANC-1 cells

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS (2011)

Journal

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

Volume 1811, Issue 12, Pages 1021-1029

Publisher

ELSEVIER SCIENCE BV

DOI: 10.1016/j.bbalip.2011.07.007

Keywords

Sphingosylphosphorylcholine; Transglutaminase-2; Keratin-8 phosphorylation and reorganization; c-Jun N-terminal kinase; Migration

Funding

National Cancer Center [NCC1110011-1]
Ministry of Education, Science & Technology, Korea [2010-0083364]
National Research Foundation of Korea [2008-2005244] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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Abstract

Sphingosylphosphorylcholine (SPC) is found at increased levels in the malignant ascites of tumor patients and induces perinuclear reorganization of keratin 8 (K8) filaments that contribute to the viscoelasticity of metastatic cancer cells. In this study, we investigated the role and molecular mechanisms of Tgase-2 in SPC-induced K8 phosphorylation and perinuclear reorganization in PANC-1 cells (PAN(WT)), and in PANC-1 cells that stably expressed shTgase-2 or Tgase-2 (PAN(shTg2) and PAN(Tg2)). SPC induces the expression of Tgase-2 in a time- and dose-dependent manner. Gene silencing of Tgase-2 or cystamine suppressed the SPC-induced phosphorylation and perinuclear reorganization of K8 and suppressed the SPC-induced migration of PANC-1 cells. An inhibitor of c-Jun N-terminal kinase (JNK), SP600125, suppressed the SPC-induced phosphorylation of serine 431 in K8 and keratin reorganization. Next, we examined the effect of Tgase-2 on JNK activation of serine 431 phosphorylation in K8. Tgase-2 gene silencing suppressed the expression of active form JNK (pJNK). Constitutive or tetracyclin-induced conditional expression of Tgase-2 increased the levels of RINK. Tgase-2 was coimmunoprecipitated with K8 and JNK. In addition, K8 was coimmunoprecipitated with Tgase-2 and JNK. JNK was also coimmunoprecipitated with K8 and Tgase-2. Overall, these results suggest that Tgase-2 is involved in SPC-induced phosphorylation and perinuclear reorganization of K8 by activating INK and forming a triple complex with K8 and JNK. Therefore, SPC-induced Tgase-2 might be a new target for modulating keratin reorganization, metastasis of cancer cells and JNK activation. (C) 2011 Elsevier B.V. All rights reserved.

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Phosphorylation of KRT8 (keratin 8) by excessive mechanical load-activated PKN (protein kinase N) impairs autophagosome initiation and contributes to disc degeneration

Di Wang, Qiliang Shang, Jianxin Mao, Chu Gao, Jie Wang, Dong Wang, Han Wang, Haoruo Jia, Pandi Peng, Mu Du, Zhuojing Luo, Liu Yang

Summary: Excessive mechanical load is a key factor in the development of mechano stress-induced pathologies such as intervertebral disc degeneration (IDD). This study demonstrates that conditional knockout of Krt8 within nucleus pulposus cells exacerbates load-induced IDD, while overexpression of Krt8 enhances the cells' resistance to overloading-induced apoptosis and degeneration. Additionally, the study reveals that the phosphorylation of KRT8 plays a crucial role in inhibiting the trafficking of RAB33B and suppressing autophagosome initiation, contributing to IDD.

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