Document Detail

Malt1 and cIAP2-Malt1 as effectors of NF-kappaB activation: kissing cousins or distant relatives?
MedLine Citation:
PMID:  19772915     Owner:  NLM     Status:  MEDLINE    
Malt1 is a multi-domain cytosolic signaling molecule that was originally identified as the target of recurrent translocations in a large fraction of MALT lymphomas. The product of this translocation is a chimeric protein in which the N-terminus is contributed by the apoptosis inhibitor, cIAP2, and the C-terminus is contributed by Malt1. Early studies suggested that Malt1 is an essential intermediate in antigen receptor activation of NF-kappaB, and that the juxtaposition of the cIAP2 N-terminus and the Malt1 C-terminus results in deregulation of Malt1 NF-kappaB stimulatory activity. Initial experimental data further suggested that the molecular mechanisms of Malt1- and cIAP-Malt1-mediated NF-kappaB activation were quite similar. However, a number of more recent studies of both Malt1 and cIAP2-Malt1 now reveal that these proteins influence NF-kappaB activation by multiple distinct mechanisms, several of which are non-overlapping. Currently available data suggest a revised model in which cIAP2-Malt1 induces NF-kappaB activation via a mechanism that depends equally on domains contributed by cIAP2 and Malt1, which confer spontaneous oligomerization activity, polyubiquitin binding, proteolytic activity, and association with and activation of TRAF2 and TRAF6 at several independent binding sites. By contrast, emerging data suggest that the wild-type Malt1 protein uniquely contributes to NF-kappaB activation primarily through the control of two proteolytic cleavage mechanisms. Firstly, Malt1 directly cleaves and inactivates A20, a negative regulator of the antigen receptor-to-NF-kappaB pathway. Secondly, Malt1 interacts with caspase-8, inducing caspase-8 cleavage of c-FLIP(L), initiating a pathway that contributes to activation of the I kappaB kinase (IKK) complex. Furthermore, data suggest that Malt1 plays a more limited and focused role in antigen receptor activation of NF-kappaB, serving to augment weak antigen signals and stimulate a defined subset of NF-kappaB dependent responses. Thus, the potent activation of NF-kappaB by cIAP2-Malt1 contrasts with the more subtle role of Malt1 in regulating specific NF-kappaB responses downstream of antigen receptor ligation.
Lara M Kingeter; Brian C Schaefer
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review     Date:  2009-09-19
Journal Detail:
Title:  Cellular signalling     Volume:  22     ISSN:  1873-3913     ISO Abbreviation:  Cell. Signal.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2009-10-23     Completed Date:  2009-12-14     Revised Date:  2014-09-10    
Medline Journal Info:
Nlm Unique ID:  8904683     Medline TA:  Cell Signal     Country:  England    
Other Details:
Languages:  eng     Pagination:  9-22     Citation Subset:  IM    
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MeSH Terms
Caspases / metabolism*
Inhibitor of Apoptosis Proteins / metabolism*
Interleukin-2 / biosynthesis
NF-kappa B / metabolism*
Neoplasm Proteins / metabolism*
Proto-Oncogene Proteins c-rel / metabolism
Grant Support
Reg. No./Substance:
0/Inhibitor of Apoptosis Proteins; 0/Interleukin-2; 0/NF-kappa B; 0/Neoplasm Proteins; 0/Proto-Oncogene Proteins c-rel; EC 3.4.22.-/Caspases

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