Robert Rickert, Ph.D.
Robert Rickert's Research Focus
The general focus of the lab is to better understand the molecular determinants of B lymphocyte differentiation in the normal and disease state. By necessity, these studies explore the in vivo environments of the primary (bone marrow) and secondary (spleen and lymphnode) lymphoid tissues, but also extend to tertiary sites to address infection, inflammation, autoimmunity and B cell neoplasia. Conditional gene targeting is widely applied to assess gene function and establish key signaling networks operating at distinct stages of B cell differentiation. In addition, in vitro cell culture systems, microscopy, flow cytometry and signal transduction approaches are utilized to examine cell-cell interactions and the molecular basis of B cell responses to antigen, cytokines, growth factors and metabolites.
Robert Rickert's Research Report
Regulation of B cell Differentiation and Transformation by the Phosphoinositide 3-kinase (PI3K) Pathway
A large effort in our lab is to understand how components of the PI3K signaling pathway specifically contribute to B cell growth, proliferation and survival as well as functions unique to B cells, namely antigen receptor assembly, signaling and antibody production. Activation of the PI3K signaling network recruits cytosolic effectors to the plasma membrane via pleckstrin homology (PH) domain-binding to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3). In particular, PDK1 has been identified as a pivotal downstream effector of PI3K that activates Akt, p70S6kinase, PKC enzymes and other targets that control cell metabolism, quiescence, proliferation and survival. The Akt kinases have also been shown to negatively regulate the activity of the FOXO transcription factors. In doing so, expression of FOXO target genes is halted, leading to enhanced cell cycle progression and survival. In B cells, we posit that the PDK1-dependent pathway acts in synergy with the PI(3,4,5)P3-dependent Btk signaling pathway, which is crucial for NF-κB activation and Ca++ mobilization. We are currently defining the relative importance and distinct functions of the PDK1- and Btk-dependent pathways in B cells.
B cell Lymphomagenesis
In recent years, we have also focused on the regulation of PI(3,4,5)P3 in B cells through the opposing functions of PI3-kinase and the 3’-inositol phosphatase and tumor suppressor PTEN. This work has been extended to include a comparative functional analysis of PTEN versus the 5’-inositol phosphatase, SHIP. Both PTEN and SHIP hydrolyze PI(3,4,5)P3; however, we found that inactivation of Pten or Ship did not result in transformation, raising the postulate that PTEN and SHIP acted cooperatively to suppress transformation. Indeed, we found that mice lacking both of these phosphatases in the B lineage developed a lethal B lymphoma. These data are the first evidence that SHIP acts as a tumor suppressor in a coordinate fashion with PTEN to dampen PI3K signaling and suppress B cell neoplasia. We are utilizing this model to address the role of antigen and tonic/inducible BCR signaling in the generation and propagation of B lymphoma cells. As most B Non-Hodgkin Lymphoma (NHL) cells do not proliferate ex vivo, we are also investigating the environmental stimuli and tissue microenvironments that drive lymphoma progression.
Functional Distinctions of IgM vs. IgG-containing B cell Receptors
Molecular studies of memory B cell activation have been hampered by their relative scarcity and lack of effective technical approaches to unveil the distinctive activation pathways employed by memory versus naïve B cells. Most memory B cells express IgG-containing B cell receptors, while naïve B cells express IgM/IgD. Relative to IgM/IgD, IgG/IgE receptors have an extended cytoplasmic tail that contains conserved phosphotyrosine (pTyr) motifs and confers enhanced survival and proliferation. We are applying cutting-edge proteomic approaches, gene silencing methods and mouse models to elucidate differences in IgM/IgD- versus IgG-based signaling. As tyrosine kinase/phosphatase activity is known to be critical for BCR signaling, our analysis is focused on determining differences in induced tyrosine phosphorylation of downstream substrates by IgG versus IgM/IgD receptors. Determining the functional importance and signaling properties of newly identified downstream effectors should greatly aid our understanding of how IgG expression directs memory B cell propagation and differentiation.
Robert Rickert's Bio
Dr. Rickert earned his Ph.D. in Immunology from the University of North Carolina, Chapel Hill in 1992. He trained as a postdoctoral fellow at The Institute for Genetics in Cologne, Germany. In 1997, Dr. Rickert was appointed as an Assistant Professor in the Division of Biological Sciences at the University of California, San Diego. Dr. Rickert was recruited to the Inflammatory and Infectious Disease Center at SBP as an Associate Professor in 2004. He served as Professor and Director of the Tumor Microenvironment and Cancer Immunology Program, Associate Dean, and Director of Academic Affairs until being recruited to Pfizer in 2017. At Pfizer, he is the SVP and Chief Scientific Officer for Cancer Immunology Discovery, Pfizer Oncology R&D.
University of Wisconsin, Madison, WI; Bachelor's Degree in Biological Sciences, Graduated with Honors in Biochemistry
University of North Carolina, Chapel Hill, NC; Ph.D, Department of Microbiology and Immunology
Adjunct Professor, Department of Pediatrics, University of California, San Diego
Miletic AV, Anzelon-Mills AN, Mills DM, Omori SA, Pedersen IM, Shin DM, Ravetch JV, Bolland S, Morse HC 3rd, Rickert RC
J Exp Med 2010 Oct 25 ;207(11):2407-20
Suppression of phosphatidylinositol 3,4,5-trisphosphate production is a key determinant of B cell anergy.
Browne CD, Del Nagro CJ, Cato MH, Dengler HS, Rickert RC
Immunity 2009 Nov 20 ;31(5):749-60
Dengler HS, Baracho GV, Omori SA, Bruckner S, Arden KC, Castrillon DH, DePinho RA, Rickert RC
Nat Immunol 2008 Dec ;9(12):1388-98
Shukla A, Chen C, Jellusova J, Leung CR, Kao E, Bhat N, Lin WW, Apgar JR, Rickert RC
JCI Insight 2019 Jul 23 ;5
A Brake for B Cell Proliferation: Appropriate responses to metabolic stress are crucial to maintain B cell viability and prevent malignant outgrowth.
Jellusova J, Rickert RC
Bioessays 2017 Nov ;39(11)
McAllister EJ, Apgar JR, Leung CR, Rickert RC, Jellusova J
J Immunol 2017 Oct 15 ;199(8):2998-3003
Boothby M, Rickert RC
Immunity 2017 May 16 ;46(5):743-755
Ramezani-Rad P, Rickert RC
Curr Opin Immunol 2017 Apr ;45:31-36
Jellusova J, Cato MH, Apgar JR, Ramezani-Rad P, Leung CR, Chen C, Richardson AD, Conner EM, Benschop RJ, Woodgett JR, Rickert RC
Nat Immunol 2017 Mar ;18(3):303-312