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Lauren Workman


lauren-workman@uiowa.edu
Mentor: Hasem Habelhah, Ph.D.
Lab Room: 1194 ML
Lab Phone: 319-335-8168

The role of TRAF2 phosphorylation in CD40-induced JNK and NF-kB activation

The various signaling events regulated by TNF-Receptor Associated Factor-2 (TRAF2) are the main research focus of the Habelhah lab. TRAF2 is a RING domain-containing adaptor protein that transduces signals emanating from many of the TNF receptor superfamily members, leading to activation of the NF-kB and MAPK pathways. Our lab mapped the TRAF2 phosphorylation sites and discovered that TRAF2 is constitutively phosphorylated in certain cancers, inducing a constant activation of NF-kB, and thus providing an elevated resistance to apoptosis that promotes cancer progression and metastasis.

My project is to determine the role of TRAF2 phosphorylation in CD40-induced JNK and NF-kB activation. CD40 is a member of the TNF receptor superfamily and is responsible for B-cell activation, proliferation, development, IgG production, and pathogen clearance. The JNK and NF-kB pathways mediate these events; however, the mechanisms by which CD40 activates these signaling pathways are not fully understood. In order to study these signaling events, I have stably expressed wild-type and phosphomutant forms of TRAF2 into TRAF2/6 double knockout B-cells. Currently, I am examining the effect of TRAF2 phosphorylation on the downstream signaling events following stimulation of CD40 with an agonistic antibody.

We believe that defining the role of TRAF2 phosphorylation in CD40-mediated JNK and NF-kB signaling will have clinical applications in B-cell specific lymphomas, leukemias, and multiple myelomas, where CD40-activated NF-kB plays a critical role in the cancer’s advancement. In addition, CD40 signaling is also implicated in inflammatory and autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus, where excessive B-cell activation can turn the body’s normal immune response on itself. Our long-term goal is to find a way to manipulate this pathway to repress the over-activation of CD40 signaling in these relevant diseases.

Abstracts:

LM Workman, K Blackwell, LQ Zhang, BS Hostager, GA Bishop, and H Habelhah. TRAF2 phosphorylation controls the CD40-mediated spatiotemporal activation of the NF-κB and JNK pathways to promote neoplastic B cell survival. 14th International TNF Conference. Quebec City, Canada. Oral presentation, 2013.

Habelhah H, Zhang LQ, Blackwell K, Workman LM. cFLIP-regulated and caspase-8-mediated limited cleavage of RIP1 promotes NF-κB activation and inhibits cell death induced by TRAIL. 103rd Annual Meeting of American Association for Cancer Research. Chicago, IL. Oral presentation, 2012.

Zhang LQ, Blackwell K, Workman LM Habelhah H. TNFα activates NF-κB through RIP1 ubiquitination- dependent and independent pathways. 103rd Annual Meeting of American Association for Cancer Research. Chicago, IL. Poster presentation, 2012.

Workman LM, Blackwell K, Zhang L, Bishop G, Habelhah H. TRAF2 phosphorylation on Serine-11 regulates CD40-induced JNK and NF-κB activation. Keystone Symposia: NF-κB Signaling and Biology: From Bench to Bedside. Whistler, BC. Poster presentation, 2012.

Publications:

Blackwell K, Zhang L, Workman LM, Ting AT, Iwai K, Habelhah H. Two coordinated mechanisms underlie TNFα-induced immediate and delayed IKK activation. Mol Cell Biol. 2013 Mar 4. [Epub ahead of print] PubMed PMID: 23459942.

Workman LM, Habelhah H. TNFR1 signaling kinetics: spatiotemporal control of three phases of IKK activation by posttranslational modification. Cell Signal. 2013 Aug;25(8):1654-64. doi: 10.1016/j.cellsig.2013.04.005. Epub 2013 Apr 21. Review. PubMed PMID: 23612498; PubMed Central PMCID: PMC3824607.



Honors and Awards

  • Scientists' Survival Skills Committee 2012-13
  • MCB Seminar Committee 2012-14
  • Holden Comprehensive Cancer Center Trainee Membership (2013-2016)
  • ECGPS Research Grant to define the role of TRAF2 phosphorylation in B-cell lymphoma progression in vivo