A novel interplay between oncogenic PFTK1 protein kinase and tumor suppressor TAGLN2 in the control of liver cancer cell motility
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摘要The PFTK1 gene encodes a cdc2-related serine/threonine protein kinase that has been shown to confer cell migratory properties in hepatocellular carcinoma (HCC). However, the prognostic value and biological mechanism by which PFTK1 promotes HCC motility remain largely unknown. Here, we showed from tissue microarray that common upregulations of PFTK1 in primary HCC tumors (n = 133/180) correlated significantly with early age onset (<= 40 years), advance tumor grading and presence of microvascular invasion (P <= 0.05). To understand downstream phosphorylated substrate(s) of PFTK1, phospho-proteins in PFTK1 expressing and knockdown Hep3B cells were profiled by two-dimensional- polyacrylamide gel electrophoresis mass spectrometric analysis. Protein identification of differential spots revealed beta-actin (ACTB) and transgelin2 (TAGLN2) as the two most profound phosphorylated changes affected by PFTK1. We verified the presence of TAGLN2 serine phosphorylation and ACTB tyrosine phosphorylation. Moreover, reduced TAGLN2 and ACTB phosphorylations in PFTK1-suppressed Hep3B corresponded to distinct actin depolymerizations and marked inhibition on cell invasion and motility. Given that TAGLN2 is a tumor suppressor whose function has been ascribed in cancer metastasis, we examined if TAGLN2 is an intermediate substrate in the biological path of PFTK1. We showed in PFTK1-suppressed cells that knockdown of TAGLN2 over-rode the inhibitory effect on cell invasion and motility, and a recovery on actin polymerization was evident. Interestingly, we also found that unphosphorylated TAGLN2 in PFTK1-suppressed cells elicited strong actin-binding ability, a mechanism that possibly halts the actin cytoskeleton dynamics. Site-directed mutagenesis of TAGLN2 suggested that PFTK1 regulates the actin-binding affinity of TAGLN2 through the S83 and S163 residues, which if mutated can significantly affect HCC cell motility. Taken together, our data propose a novel, oncogene-tumor suppressor interplay, where oncogenic PFTK1 confers HCC cell motility through inactivating the actin-binding motile suppressing function of TAGLN2 via phosphorylation. Oncogene (2011) 30, 4464-4475; doi: 10.1038/onc.2011.161; published online 16 May 2011
著者Leung WKC, Ching AKK, Chan AWH, Poon TCW, Mian H, Wong AST, To KF, Wong N
期刊名稱Oncogene
出版年份2011
月份11
日期1
卷號30
期次44
出版社Nature Publishing Group: Open Access Hybrid Model Option B
頁次4464 - 4475
國際標準期刊號0950-9232
電子國際標準期刊號1476-5594
語言英式英語
關鍵詞actin; cell migration; hepatocellular carcinoma; PFTK1; TAGLN2
Web of Science 學科類別Biochemistry & Molecular Biology; BIOCHEMISTRY & MOLECULAR BIOLOGY; Cell Biology; CELL BIOLOGY; Genetics & Heredity; GENETICS & HEREDITY; Oncology; ONCOLOGY

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