Binding of Par-4 to the actin cytoskeleton is essential for Par-4/Dlk-mediated apoptosis
- PMID: 15817164
- DOI: 10.1016/j.yexcr.2005.01.012
Binding of Par-4 to the actin cytoskeleton is essential for Par-4/Dlk-mediated apoptosis
Abstract
Prostate apoptosis response-4 (Par-4) is a 38-kDa protein originally identified as a gene product upregulated in prostate cancer cells undergoing apoptosis. Cell death mediated by Par-4 and its interaction partner DAP like kinase (Dlk) is characterized by dramatic changes of the cytoskeleton. To uncover the role of the cytoskeleton in Par-4/Dlk-mediated apoptosis, we analyzed Par-4 for a direct association with cytoskeletal structures. Confocal fluorescence microscopy revealed that endogenous Par-4 is specifically associated with stress fibers in rat fibroblasts. In vitro cosedimentation analyses and in vivo FRET analyses showed that Par-4 directly binds to F-actin. Actin binding is mediated by the N-terminal 266 amino acids, but does not require the C-terminal region of Par-4 containing the leucine zipper and the death domain. Furthermore, the interaction of Par-4 with actin filaments leads to the formation of actin bundles in vitro and in vivo. In rat fibroblasts, this microfilament association is essential for the pro-apoptotic function of Par-4, since both disruption of the actin cytoskeleton by cytochalasin D treatment and overexpression of Par-4 constructs impaired in actin binding result in a significant decrease of apoptosis induction by Par-4 and Dlk. We propose a model, in which Par-4 recruits Dlk to stress fibers, leading to enhanced phosphorylation of the regulatory light chain of myosin II (MLC) and to the induction of apoptosis.
Similar articles
-
Par-4-mediated recruitment of Amida to the actin cytoskeleton leads to the induction of apoptosis.Exp Cell Res. 2005 Dec 10;311(2):177-91. doi: 10.1016/j.yexcr.2005.09.010. Epub 2005 Oct 14. Exp Cell Res. 2005. PMID: 16229834
-
DAP-like kinase, a member of the death-associated protein kinase family, associates with centrosomes, centromers, and the contractile ring during mitosis.Eur J Cell Biol. 2003 Sep;82(9):447-59. doi: 10.1078/0171-9335-00332. Eur J Cell Biol. 2003. PMID: 14582533
-
Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis.Oncogene. 1999 Dec 2;18(51):7265-73. doi: 10.1038/sj.onc.1203170. Oncogene. 1999. PMID: 10602480
-
The regulation of death-associated protein (DAP) kinase in apoptosis.Eur Cytokine Netw. 2002 Oct-Dec;13(4):398-400. Eur Cytokine Netw. 2002. PMID: 12517721 Review.
-
Effects of cadmium on the actin cytoskeleton in renal mesangial cells.Can J Physiol Pharmacol. 2013 Jan;91(1):1-7. doi: 10.1139/cjpp-2012-0229. Epub 2013 Jan 1. Can J Physiol Pharmacol. 2013. PMID: 23368511 Review.
Cited by
-
Involvement of the Actin Machinery in Programmed Cell Death.Front Cell Dev Biol. 2021 Feb 9;8:634849. doi: 10.3389/fcell.2020.634849. eCollection 2020. Front Cell Dev Biol. 2021. PMID: 33634110 Free PMC article. Review.
-
Epigenetic silencing of tumor suppressor Par-4 promotes chemoresistance in recurrent breast cancer.J Clin Invest. 2018 Oct 1;128(10):4413-4428. doi: 10.1172/JCI99481. Epub 2018 Aug 27. J Clin Invest. 2018. PMID: 30148456 Free PMC article.
-
Restoration of DAP Kinase Tumor Suppressor Function: A Therapeutic Strategy to Selectively Induce Apoptosis in Cancer Cells Using Immunokinase Fusion Proteins.Biomedicines. 2017 Oct 4;5(4):59. doi: 10.3390/biomedicines5040059. Biomedicines. 2017. PMID: 28976934 Free PMC article. Review.
-
The cell biology of aging.Mol Biol Cell. 2015 Dec 15;26(25):4524-31. doi: 10.1091/mbc.E14-06-1084. Mol Biol Cell. 2015. PMID: 26668170 Free PMC article. Review.
-
Hierarchical scaffolding of an ERK1/2 activation pathway.Cell Commun Signal. 2013 Aug 29;11:65. doi: 10.1186/1478-811X-11-65. Cell Commun Signal. 2013. PMID: 23987506 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases