The alternative splice variant of DAPK-1, s-DAPK-1, induces proteasome-independent DAPK-1 destabilization.

Lin, Yao; Stevens, Craig; Harrison, Ben; Pathuri, Suresh; Amin, Eliana; Hupp, Ted R.

Abstract

Death-associated protein kinase 1 (DAPK-1) is a Ca2+/CaM-regulated kinase involved in multiple cellular signalling pathways that trigger cell survival, apoptosis, and autophagy. An alternatively spliced product expressed from the dapk1 locus, named s-DAPK-1, does not contain the kinase domain but has part of the DAPK-1 ankyrin-repeat and a novel polypeptide tail extension which is processed proteolytically in vivo. Cleavage of this polypeptide tail from s-DAPK-1 can regulate the ability of the protein to mimic one of the biological functions of DAPK-1 in promoting membrane blebbing. The full-length DAPK-1 protein is a relatively long-lived protein whose half-life is regulated by stress-activated signals from TNFR1 or HSP90 that can promote DAPK-1 protein degradation. Transfection of s-DAPK-1 into cells can also have a direct effect on DAPK-1 protein itself by promoting DAPK-1 de-stabilization. This effect does not require the novel polypeptide tail-extension of s-DAPK-1, as the core ankyrin-repeat containing region of s-DAPK-1 is sufficient to promote DAPK-1 protein de-stabilization. Conversely, the minimal domain on full-length DAPK-1 that responds to the effect of s-DAPK-1 is not the ankyrin-repeat domain but the core kinase domain of DAPK-1. The de-stabilization of DAPK-1 by s-DAPK-1 is not dependent upon the proteasome. However, s-DAPK-1 itself is a very short-lived protein which is regulated by a proteasomal-dependent pathway. Together, these data identify a novel function of s-DAPK-1 in controlling the half-life of DAPK-1 protein itself and indicate that the degradation of each gene product is controlled by two distinct degradation pathways.

Citation

Lin, Y., Stevens, C., Harrison, B., Pathuri, S., Amin, E., & Hupp, T. R. (2009). The alternative splice variant of DAPK-1, s-DAPK-1, induces proteasome-independent DAPK-1 destabilization. Molecular and Cellular Biochemistry, 328(1-2), 101-107. https://doi.org/10.1007/s11010-009-0079-4

• Journal Article Type: Article
• Online Publication Date: Mar 8, 2009
• Publication Date: Mar 8, 2009
• Deposit Date: Aug 2, 2016
• Journal: Molecular and Cellular Biochemistry
• Print ISSN: 0300-8177
• Electronic ISSN: 1573-4919
• Publisher: BMC
• Peer Reviewed: Peer Reviewed
• Volume: 328
• Issue: 1-2
• Pages: 101-107
• DOI: https://doi.org/10.1007/s11010-009-0079-4
• Keywords: DAPK-1p53, Degradation, Proteasomes, s-DAPK-1
• Public URL: http://researchrepository.napier.ac.uk/Output/322328
• Publisher URL: http://dx.doi.org/10.1007/s11010-009-0079-4