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Pathway Description
D4-GDI Signaling Pathway
Homo sapiens
Protein Pathway
Perforin protein forms pores in the membrane to allow for granzyme B to enter the cell. Granzymes induce apoptosis by activating caspases. D4-GDP dissociation inhibitor (D4-GDI) is a negative regulator of ras-related Rho Family of GTPases. D4-GDI binds Rho GTPases to keep the Rho protein in a GDP-bound and inactivate state. Caspase 3 cleaves D4-GDI into two fragments of 5 kDa and 23 kDa size. The 23 kDa fragment translocates to the nucleus to activate Jun kinase, a regulator of apoptosis. Poly (ADP-ribose) polymerase-1 (PARP) is a substrate for caspase-3. Caspase-3 cleaves PARP into various fragments, this is a hallmark of apoptosis. PARP functions to detect and repair DNA damage. Cleavage of PARP by caspase prevents DNA repair, contributing to cell death. RHO GTPases become activated when released from D4-GDI upon cleavage by caspase-3. RHO GTPases mediate cytoskeleton changes leading to apoptosis and cell death. .
References
D4-GDI Signaling Pathway References
https://cgap.nci.nih.gov/Pathways/BioCarta/h_d4gdiPathway
Barry M, Heibein JA, Pinkoski MJ, Lee SF, Moyer RW, Green DR, Bleackley RC: Granzyme B short-circuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving Bid. Mol Cell Biol. 2000 Jun;20(11):3781-94.
Pubmed: 10805722
Chaitanya GV, Steven AJ, Babu PP: PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Commun Signal. 2010 Dec 22;8:31. doi: 10.1186/1478-811X-8-31.
Pubmed: 21176168
Coleman ML, Olson MF: Rho GTPase signalling pathways in the morphological changes associated with apoptosis. Cell Death Differ. 2002 May;9(5):493-504. doi: 10.1038/sj/cdd/4400987.
Pubmed: 11973608
Kwon KB, Park EK, Ryu DG, Park BH: D4-GDI is cleaved by caspase-3 during daunorubicin-induced apoptosis in HL-60 cells. Exp Mol Med. 2002 Mar 31;34(1):32-7. doi: 10.1038/emm.2002.5.
Pubmed: 11989976
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