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.

Role of Melanoma Inhibitor of Apoptosis (ML-IAP) Protein, a Member of the Baculoviral IAP Repeat (BIR) Domain Family, in the Regulation of C-RAF Kinase and Cell Migration*

It is shown that ML-IAP can directly bind to C-RAF and that ML -IAP depletion leads to an increase in C- RAF protein levels, MAPK activation, and cell migration in melanoma cells.

Regulation of Apoptosis by Inhibitors of Apoptosis (IAPs)

The role of IAP in regulating apoptosis in Drosophila and Mammals is highlighted and X-linked IAP (XIAP) and cellular IAPs (cIAPs) appeared to be important determinants of the response of cells to endogenous or exogenous cellular injuries.

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.

IAPs regulate the plasticity of cell migration by directly targeting Rac1 for degradation

X‐linked IAP (XIAP) and cellular IAP1 (c‐IAP1) directly bind to Rac1 in a nucleotide‐independent manner to promote its polyubiquitination at Lys147 and proteasomal degradation, unveiling an evolutionarily conserved role of IAPs in controlling Rac1 stability thereby regulating the plasticity of cell migration and morphogenesis.

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.



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.

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.

XIAP-deficiency leads to delayed lobuloalveolar development in the mammary gland

It is found that XIAP expression is developmentally regulated in the mammary gland and a potential role for this gene during mammopoiesis is investigated using targeted mice.