Project

protease; proliferation; lymphoma; breast cancer; caspase; metacaspase; paracaspase; ADAMTS; mammary gland development

Lead
Lay summary
Enzymes of the protease family have important roles in the control of vital cellular processes. The activities of the intracellular proteases MALT1 and caspase-8, for example, both control lymphocyte proliferation, whilst extracellular, secreted proteases of the MMP and ADAM family also play diverse roles in tumorigenesis. Thus, proteases emerge as enzymes that have pivotal roles in regulating cellular growth and proliferation. The laboratory of Margot Thome-Miazza has recently demonstrated for the first time a protease activity for the protein MALT1, and shown that inhibition of MALT1 blocks lymphocyte activation, and proliferation and survival of diffuse large B-cell lymphoma (DLBCL) cell lines of the activated B-cell (ABC) subtype. Surprisingly, inhibition of another class of proteases using chemical inhibitors also impaired cellular survival of ABC DLBCL, but the protease involved and its substrates are largely unknown. Therefore, one part of this research module will aim at the identification of the protease and its substrates involved in normal or malignant lymphocyte proliferation. The laboratory of Nicolas Fasel has recently uncovered a protease activity for a Leishmania major homologue of a protein that is part of a signaling complex controlling cellular growth and proliferation. Inhibition of this signaling pathway using specific drugs is clinically relevant for immunosuppression, and also an attractive target for cancer therapy since dysregulation of this pathway occurs in several types of human cancers. Another aim of this joint project is therefore to address whether the putative protease activity might contribute to cellular growth regulation. The laboratory of Cathrin Brisken identified the secreted protease ADAMTS18 in a screen for genes that are downstream of progesterone and RANKL-induced signaling in the mouse mammary epithelium. ADAMTS18 has been implicated as a tumor suppressor in human breast cancer, yet its substrates and its role in normal development and tumorigenesis are unknown. The laboratory has generated mice with a conditional ADAMTS18 allele, and will test the hypothesis that the ADAMTS18 has a biphasic role in mammary tumorigenesis through modulation of TGF? signaling. Collectively, the complementary (biochemical and genetic) approaches taken within this research module might identify novel protease activities relevant for the immune response and cellular proliferation, and thereby identify interesting therapeutic targets for immunomodulation and the treatment of human malignancies.

Direct link to Lay Summary

Last update: 21.02.2013

Self-organised

Self-organised

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Number	Title	Start	Funding scheme

Caspases, metacaspases and paracaspases are members of a larger family of proteases that have important roles in the control of cellular proliferation and survival. The human paracaspase MALT1 and the caspase family member caspase-8, for example, both control lymphocyte proliferation. Recently, a protease-like domain with homology to metacaspases has been identified in the human protein Raptor, which may be relevant to its established role in cellular growth. In addition to intracellular proteases, secreted proteases of the ADAM family also play diverse roles in tumorigenesis. Thus, proteases emerge as enzymes that have pivotal roles in regulating cellular growth and proliferation. The laboratory of Margot Thome-Miazza has recently demonstrated for the first time a protease activity for the paracaspase MALT1, and shown that inhibition of MALT1 blocks lymphocyte activation, but also the growth and survival of diffuse large B-cell lymphoma (DLBCL) cell lines of the activated B-cell (ABC) subtype, in which MALT1 is constitutively active. Surprisingly, inhibition of caspases using the pan-caspase inhibitor z-VAD also impaired cellular survival of ABC DLBCL, but the caspase involved and its substrates are largely unknown. Therefore, one part of this research module will aim at the identification of the caspase and its substrates involved in normal or malignant lymphocyte proliferation. The laboratory of Nicolas Fasel has recently uncovered a proteolytic activity for the Leishmania Major homologue of the mammalian Raptor protein. Raptor (regulatory-associated protein of TOR) is part of the TOR (target of rapamycin) signaling complex that is known to control cellular growth and proliferation. Inhibition of this signaling pathway using rapamycin is clinically relevant for immuno-suppression, and TOR is also an attractive target for cancer therapy since dysregulation of TOR signaling occurs in several types of human cancers. This suggests the possibility that the protease activity of Raptor might contribute to TOR-dependent cellular growth regulation. Another aim of this project is therefore to address whether lymphocyte growth is affected by catalytically inactivate mutants of Raptor.The laboratory of Cathrin Brisken identified the secreted protease ADAMTS18 in a screen for genes that are downstream of progesterone and RANKL-induced signaling in the mouse mammary epithelium. ADAMTS18 has been implicated as a tumor suppressor in human breast cancer, yet its substrates and its role in normal development and tumorigenesis are unknown. The laboratory has generated an ADAMTS deficient mouse strain, both straight and floxed, and proposes to analyse the role of this protease in normal mammary gland development and tumorigenesis.Collectively, the parallel approaches taken within this research module might identify novel proteolytic activities relevant for the immune response and cellular proliferation, and thereby identify interesting therapeutic targets for immuno-modulation and the treatment of human malignancies.