Immune-Cell Signaling & Regulation
To maintain homeostasis within the body and protect against infection and cancer, cells respond to a wide array of signals in their environment. This signaling is especially complex in the immune system, with myeloid cells and lymphocytes responding to direct contact with other cells and to soluble factors, such as hormones, antigens, cytokines, and chemokines, which activate signaling programs subject to positive and negative feedback regulation. We are particularly interested in the earliest signaling events that occur at the membrane, starting with receptor ligation and the activation of the membrane-proximal protein tyrosine kinases (i.e. Src, Lyn, Fyn, Hck, Fgr, Syk). We also focus on how receptor ligation influences signal output, how networks of kinases and phosphatases are mobilized specifically in response to different types of stimuli, and how negative feedback processes restrain inflammation.
Revealing the mechanisms orchestrating this complex signal integration and the context-specific functions of these signaling molecules will be instrumental to furthering our understanding of autoimmunity and the immunosuppressive tumor microenvironment and developing new ways to treat these conditions.
Select Publications
A dominant function of LynB kinase in preventing autoimmunity
Brian*, Sauer*, Greene* (co-first), Senevirathne, Lindstedt, Funk, Ruis, Ramirez, Auger, Swanson, Nunez, Moriarity, Lowell, Binstadt, Freedman
(2022) Sci Adv. 8(16):eabj5227. PMID:35452291
SH3-domain mutations selectively disrupt Csk homodimerization or PTPN22 binding
Brian, Sjaastad, Freedman (2022) Sci Rep. 12:5875. PMID:35393453
Regulation of myeloid-cell activation (review)
Greene, Brian, Senevirathne, Freedman (2021) Curr Opin Immunol. 73:34-42. PMID:34601225
The Src-family kinase Lyn in immunoreceptor signaling (review)
Brian, Freedman (2021) Endocrinology. 162(10):bqab152. PMID:34320188
Immunopharmacology and quantitative analysis of tyrosine kinase signaling (review/protocol)
Brian, Guerrero, Freedman (2020) Curr Protoc Immunol. 130(1):e104. PMID:32931655
Unique-region phosphorylation targets LynA for rapid degradation, tuning its expression and signaling in myeloid cells
Brian, Jolicoeur, Guerrero, Nunez, Sychev, Hegre, Sætrom, Habib, Drake, Schwertfeger, Freedman (2019) eLife. 8:e46043. PMID:31282857
LynA regulates an inflammation-sensitive signaling checkpoint in macrophages
Freedman (co-corresponding), Tan, Skrzypczynska, Manz, Sjaastad, Goodridge, Lowell, Weiss (2015) eLife. 4:e09183. PMID:26517880
Inhibition of the kinase Csk in thymocytes reveals a requirement for actin remodeling in the initiation of full TCR signaling
Tan, Manz, Freedman, Zhang, Shokat, Weiss (2014) Nat Immunol. 15(2):186-194. PMID:24317039
STIM1, PKC-δ and RasGRP set a threshold for proapoptotic Erk signaling during B cell development
Limnander, Depeille, Freedman, Liou, Leitges, Kurosaki, Roose, Weiss (2011) Nat Immunol. 12(5):425-433. PMID:21441934
ZAP-70: an essential kinase in T-cell signaling (review)
Wang, Kadlecek, Au-Yeung, Goodfellow, Hsu, Freedman, Weiss (2010) Cold Spring Harb Perspect Biol. 2:a002279. PMID:20452964