X-linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility

  title={X-linked and cellular IAPs modulate the stability of C-RAF kinase and cell motility},
  author={Taner Dogan and Gregory S. Harms and Mirko Hekman and Christiaan Karreman and Tripat Kaur Oberoi and Emad S Alnemri and Ulf R{\"u}diger Rapp and Krishnaraj Rajalingam},
  journal={Nature Cell Biology},
Inhibitor of apoptosis proteins (IAP) are evolutionarily conserved anti-apoptotic regulators. C-RAF protein kinase is a direct RAS effector protein, which initiates the classical mitogen-activated protein kinase (MAPK) cascade. This signalling cascade mediates diverse biological functions, such as cell growth, proliferation, migration, differentiation and survival. Here we demonstrate that XIAP and c-IAPs bind directly to C-RAF kinase and that siRNA-mediated silencing of XIAP and c-IAPs leads… 
Increased migration and motility in XIAP-null cells mediated by the C-RAF protein kinase
It is suggested that XIAP is not necessary for control of the apoptotic signalling cascade, however it does have a critical role in controlling cell migration and motility that cannot be compensated for in XIAP-knockout cells.
Regulation of Cell Death and Immunity by XIAP.
X-chromosome-linked inhibitor of apoptosis protein (XIAP) controls cell survival in several regulated cell death pathways and coordinates a range of inflammatory signaling events, making it an attractive drug target in tumors and inflammatory diseases.
X-linked Inhibitor of Apoptosis Protein negatively regulates neuronal differentiation through interaction with cRAF and Trk
It is demonstrated that X-linked Inhibitor of apoptosis protein plays a new role as a negative regulator of neurotrophin-induced neurite outgrowth and neuronal differentiation in developing neurons.
X-linked Inhibitor of Apoptosis Protein (XIAP) Mediates Cancer Cell Motility via Rho GDP Dissociation Inhibitor (RhoGDI)-dependent Regulation of the Cytoskeleton*
A deficiency of XIAP expression in human cancer cells by either knock-out or knockdown leads to a marked reduction in β-actin polymerization and cytoskeleton formation, which provides novel insights into the molecular mechanisms by which XIAP regulates cancer invasion.
The ubiquitin ligase HERC1 regulates cell migration via RAF-dependent regulation of MKK3/p38 signaling
It is shown that the ubiquitin ligase HERC1 regulates the p38 signaling pathway, and that this regulation is mediated by the MAPK kinase MKK3, and a crosstalk between RAF/MKK3/p38 signaling pathways during cell migration is demonstrated.
Characterizing the interaction between RanBPM and c-Raf
It is shown that the N-terminus, LisH/CTLH and CRA domains of RanBPM are required for downregulation of c-Raf and that RanB PM interacts directly with c- Raf through its CRA domain, and that MAEA, another CTLH complex member, associates with c -Raf.
Ubiquitin-dependent regulation of Cdc42 by XIAP
It is demonstrated that the highly conserved, RING domain containing E3 ubiquitin ligase XIAP controls the protein stability of Cdc42, a well-studied member of the family that controls filopodia formation and cell migration.
Role for X-linked Inhibitor of Apoptosis Protein Upstream of Mitochondrial Permeabilization*
It is shown that in response to loss of survival signals provided by cell adhesion, endogenous XIAP translocates from the cytosol into a mitochondrial 400-kDa complex and that this occurs very early in the apoptosis process.
IAP Proteins and Their Therapeutic Potential
IAP antagonists have successfully passed initial safety scrutiny in clinical trials and are about to enter a critical phase in their development in which their antitumor efficacy will be tested in the hopes of providing novel treatments for cancer patients.


Interaction and stabilization of X-linked inhibitor of apoptosis by Raf-1 protein kinase.
The physical interaction between Raf-1 and XIAP in vitro and in vivo in mammalian cells is described and it is demonstrated that Raf-2 phosphorylates and prevents XIAP degradation in response to different apoptotic triggers.
Prohibitin is required for Ras-induced Raf–MEK–ERK activation and epithelial cell migration
The data show an unexpected role of prohibitin in the activation of the Ras–Raf signalling pathway and in modulating epithelial cell adhesion and migration.
Geldanamycin-induced destabilization of Raf-1 involves the proteasome.
Signaling through this pathway was inhibited by GA, concomitant with loss of Raf-1 protein, but was restored if Raf-2 was protected from GA-induced degradation by proteasome inhibitors, and showed a laddering pattern consistent with its polyubiquitination.
Destabilization of Raf-1 by geldanamycin leads to disruption of the Raf-1-MEK-mitogen-activated protein kinase signalling pathway
Interaction between HSP90 and Raf-1 is a sine qua non for Raf stability and function as a signal transducer and that the effects observed cannot be attributed to a general impairment of protein kinase function.
V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors.
  • O. Grbovic, A. Basso, N. Rosen
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2006
It is suggested that activated mutated B-Raf proteins are incompetent for folding in the absence of Hsp90, thus suggesting that the chaperone is required for the clonal evolution of melanomas and other tumors that depend on this mutation.
A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis
It is shown that XIAP associates with the active caspase-9–Apaf-1 holoenzyme complex through binding to the amino terminus of the linker peptide on the small subunit of caspite-9, which becomes exposed after proteolytic processing of procaspases-9 at Asp 315.
Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin.
The data show that B-RAF is an important target for 17-AAG in human cancer, and it is shown that (V600E)B-RAf is an Hsp90 client protein that requires HSp90 for its folding and stability.
Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family
Current knowledge of the caspase‐inhibitory potential of the human IAPs is reviewed and it is shown that XIAP is probably the only bona fide casp enzyme inhibitor, suggesting that the other family members never gained the ability to directly inhibit caspases activity.
Characterization of XIAP-Deficient Mice
The changes in c-IAP1 and c- IAP2 expression may provide functional compensation for loss of XIAP during development or in the induction of apoptosis, suggesting that there exists a compensatory mechanism that leads to upregulation of other family members when XIAP expression is lost.