Molecular pathways: targeting MALT1 paracaspase activity in lymphoma

Clin Cancer Res. 2013 Dec 15;19(24):6662-8. doi: 10.1158/1078-0432.CCR-12-3869. Epub 2013 Sep 4.

Abstract

MALT1 mediates the activation of NF-κB in response to antigen receptor signaling. MALT1, in association with BCL10 and CARD11, functions as a scaffolding protein to activate the inhibitor of IκB kinase (IKK) complex. In addition, MALT1 is a paracaspase that targets key proteins in a feedback loop mediating termination of the NF-κB response, thus promoting activation of NF-κB signaling. Activated B-cell subtype of diffuse large B-cell lymphomas (ABC-DLBCL), which tend to be more resistant to chemotherapy, are often biologically dependent on MALT1 activity. Newly developed MALT1 small-molecule inhibitors suppress the growth of ABC-DLBCLs in vitro and in vivo. This review highlights the recent advances in the normal and disease-related functions of MALT1. Furthermore, recent progress targeting MALT1 proteolytic activity raises the possibility of deploying MALT1 inhibitors for the treatment of B-cell lymphomas and perhaps autoimmune diseases that involve increased B- or T-cell receptor signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Apoptosis Regulatory Proteins
  • B-Cell CLL-Lymphoma 10 Protein
  • CARD Signaling Adaptor Proteins / genetics
  • CARD Signaling Adaptor Proteins / metabolism
  • Caspases / genetics*
  • Caspases / metabolism
  • Guanylate Cyclase / genetics
  • Guanylate Cyclase / metabolism
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Molecular Targeted Therapy*
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • NF-kappa B / metabolism
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Receptors, Antigen / metabolism
  • Receptors, Antigen, T-Cell
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • B-Cell CLL-Lymphoma 10 Protein
  • BCL10 protein, human
  • CARD Signaling Adaptor Proteins
  • NF-kappa B
  • Neoplasm Proteins
  • Receptors, Antigen
  • Receptors, Antigen, T-Cell
  • Caspases
  • MALT1 protein, human
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • CARD11 protein, human
  • Guanylate Cyclase