Dr. Linda McAllister-Lucas is an NIH-funded physician-scientist who investigates how dysregulated intracellular signaling contributes to inflammatory and neoplastic disease. She co-directs a research laboratory with Dr. Peter Lucas, a member of the faculty in the Department of Pathology. Their joint laboratory, the Lucas / McAllister Lab, comprises ten scientists at varying stages of training, and their group is pursuing two related areas of research.
The Molecular Pathogenesis of B-Cell Lymphoma. The t(11;18) recurrent chromosomal translocation occurs in up to 40% of cases of the B-cell malignancy mucosa-associated lymphoid tissue (MALT) lymphoma and is associated with resistance to therapy and tendency to disseminate. This translocation results in the creation of the chimeric API2-MALT1 fusion oncoprotein. The team is studying the molecular mechanism by which API2-MALT1 promotes oncogenesis with the goals of (a) providing insight into the molecular pathogenesis of lymphoma and (b) providing the rationale for the design of novel agents for treating refractory disease. They recently discovered that the API2-MALT1 fusion oncoprotein proteolytically cleaves and activates the NF-kappaB-inducing kinase (NIK) kinase and that this cleavage results in constitutive activation of the noncanonical NF-kappaB signaling pathway. Their work was published in the leading journal Science. This landmark manuscript was then selected for the Faculty of 1000 and was featured as Editor’s Choice in Science Signaling. In collaboration with a team at the University of Michigan, they then also went on to demonstrate that API2-MALT1-mediated cleavage of a second substrate, LIMA1, is also critical to API2-MALT1 oncogenic function. This work was published in Nature Communications. More recently, they elucidated a novel role for receptor-interacting protein 1 (RIP1), a central regulator of tumor necrosis factor (TNF)-dependent effects on cellular survival, in the pathogenesis of MALT lymphoma. Specifically, they found that similar to TNF receptor stimulation, expression of API2-MALT1 induces the ubiquitination of RIP1 at lysine (K) 377. RIP1 ubiquitination, which allows the ubiquitin chains on RIP1 to scaffold critical downstream proteins and thereby stimulate the prosurvival canonical NF-kappaB pathway, is required for the AP12-MALT1 oncoprotein to promote survival of B cells. Intriguingly, constitutive RIP1 ubiquitination was recently demonstrated to be a characteristic of several solid tumors, and now their study implicates, for the first time, RIP1 ubiquitination as a critical event in lymphomagenesis. Together, these studies have revealed new potential therapeutic targets (MALT1 protease, NIK kinase, and RIP1 kinase) for refractory disease, and work is ongoing to investigate the efficacy of inhibiting these targets in preventing lymphoma growth and survival.
The CARMA-Bcl10-MALT1 Signaling Complex in Inflammatory and Neoplastic Disease. The team discovered the CARMA1-Bcl10-MALT1 (CBM) signalosome, a complex of three proteins that plays a critical role in innate immunity by mediating antigen receptor-dependent stimulation of the prosurvival transcription factor, NF-kappaB, in lymphocytes. Dysregulation of this complex, as a result of mutation or chromosomal translocation involving the CARMA1, BCL10, or MALT1 genes, leads to B-cell lymphoma. Later, they made the innovative discovery that a CBM signalosome also functions outside of lymphocytes by operating downstream of specific G-protein coupled receptors (GPCRs) in non-immune cells. In this case, the nonlymphoid-specific homologue CARMA3 substitutes for the lymphocyte-specific CARMA1. They are now actively studying the contribution of GPCR-induced, CBM-dependent stimulation of NF-kappaB to a variety of inflammatory and neoplastic diseases and exploring the utility of inhibiting the CBM complex as a new approach to treatment of these conditions. Specifically, they have elucidated a new role for the CBM complex in mediating progression and metastasis of a variety of solid tumors including breast cancer and sarcoma. In addition, the McAllister-Lucas research group has discovered a new role for MALT1 proteolytic activity in promoting GPCR-induced endothelial permeability, a finding that was recently published in and featured on the cover of Cell Reports.
Education & Training
- Fellowship-University of Michigan, Ann Arbor, MI
- Residency-University of Michigan, Ann Arbor, MI
- MD-Vanderbilt University, Nashville, TN
- PhD-Vanderbilt University, Nashville, TN
- GPCR Signaling Through a Novel NF-B Pathway
- A Novel Signaling Pathway Mediating Hypertension- and Obesity-Dependent Insulin Resistance
- Angiotensin II Signaling Through a Novel NF-B Pathway
- Multiple Roles of the API2 Moiety in API2-MALT1-Mediated Lymphomagenesis
- Molecular pathogenesis of Non-Hodgkin Lymphoma
- Molecular mechanisms by which inflammation promotes tumor development and metastasis