About

Dr. Tanya Freedman is an Associate Professor in the Department of Pharmacology at the University of Minnesota. She is affiliated with the Center for Immunology, Masonic Cancer Center, and Center for Autoimmune Diseases Research at UMN. She completed her AB with honors in Biochemistry at Bowdoin College and earned her PhD in Molecular and Cell Biology at the University of California, Berkeley, where she studied the structural biology of Ras-activating proteins. Her postdoctoral fellowship at the University of California, San Francisco, involved discovering a mechanism by which the Src-family kinase LynA tunes macrophage sensitivity to pro-inflammatory activation, with implications for myeloid-cell hypersensitization in autoimmune disease. Her research focuses on the mechanisms by which myeloid cells and lymphocytes integrate positive- and negative-regulatory signals to achieve tissue-specific functions and drive pathologies such as autoimmune diseases, inflammatory arthritis, and breast cancer. Her lab investigates how immune cells discriminate between different extracellular molecules, achieve tissue-specific functions, and how immune responses become dysregulated in disease. Particular interest is given to mechanisms regulated by tyrosine kinases like LynA and LynB, and phosphatases such as PTPN22 and SHP-1, in myeloid cells including macrophages, dendritic cells, and mast cells.

Research topics

• Sociology
• Political Science
• Immunology
• Economics
• Medicine
• Virology
• Engineering
• Business
• Economic growth
• Engineering ethics
• Cell biology
• Biology
• Public relations
• Law
• Cancer research

Selected publications

• Basal phosphorylation of SHIP1 by Lyn suppresses proinflammatory signaling in the absence of a phagocytic synapse

  The Journal of Immunology · 2026-03-01

  articleOpen accessSenior author

  Microscale engagement of the hemi-immunoreceptor tyrosine-based activation motif-containing receptor Dectin-1 by fungal particles activates Src-family kinases (SFKs) and Syk, drives second-messenger generation, and induces downstream Erk and Akt signaling and proinflammatory responses in macrophages. To avoid inappropriate activation in the absence of a pathogenic threat, macrophages restrict signaling in response to low-valency ligands. To examine how SFKs regulate this sensitivity threshold, we compared signaling induced by pharmacological SFK activation with signaling triggered by depleted zymosan, a high-valency β-glucan particle that engages Dectin-1 to form a phagocytic synapse. We found that particulate engagement of Dectin-1 protected the inhibitory ITIM-associated phosphatase SHIP1 from phosphorylation by SFKs, allowing robust activation of Erk and Akt and proinflammatory induction. In contrast, receptor-independent SFK activation induced phosphorylation of SHIP1 and failed to amplify signaling downstream of PLCγ2 and PI3K. Although multiple SFKs could phosphorylate SHIP1, Lyn uniquely maintained the basal set-point of SHIP1 phosphorylation, thereby keeping PIP3 levels low and suppressing basal Erk and Akt signaling. This Lyn-dependent regulation was essential for suppressing Akt activation and balancing signaling through the Erk and Akt pathways in the absence of a phagocytic synapse. In contrast, antimicrobial responses to particulate stimuli, including second-messenger signaling, Erk/Akt, and proinflammatory outputs, did not strictly require Lyn expression. These findings highlight the unique role of Lyn in limiting spurious proinflammatory signaling and shed light on a mechanism by which macrophages selectively respond to high-valency particulate ligands that override this basal inhibitory program.

  PublisherDOI

• Dose-dependent activation of Syk and SHIP1 by LynA and LynB at steady state creates a thresh-old for macrophage signaling in the absence of receptor engagement

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-27

  articleOpen accessSenior authorCorresponding

  LynA-knockout and LynB-knockout mice, each expressing only one of two isoforms of the Src-family kinase (SFK) Lyn, have differential progression to autoimmunity. It is unclear, however, whether isoform-specificity or Lyn dose underlies differential signaling in the single-isoform knockouts. To address this question, we generated a series of Lyn-knockout mice with a varying LynA and LynB expression and tested macrophage signaling in response to pharmacological pan-SFK activation. We found that the magnitude of initiating signaling is a function of the combined basal expression of LynA and LynB, with the two isoforms equally capable of phosphorylating positive-regulatory Syk and negative-regulatory SHIP1. While expression of either isoform restored basal and SFK-initiated downstream signaling, WT-like levels of Erk and Akt signaling were enabled by expression of any amount of Lyn and insensitive to further upregulation of either isoform. Thus, either LynA or LynB expression at steady state leads to balanced activation of positive- and negative-regulatory signaling, setting a maximal response in the absence of a true microbial encounter. Summary Sentence: Total expression of LynA and LynB determines the steady-state phosphorylation of the activating kinase Syk and the inhibitory phosphatase SHIP1, capping signaling in the absence of a microbial encounter.

  PublisherOA PDFDOI

• Steady-state phosphorylation of SHIP1 by Lyn restricts macrophage activation in the absence of a phagocytic synapse

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-22 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Microscale engagement of the hemi-ITAM-containing receptor Dectin-1 by a fungus-derived particle initiates signaling through the Src-family kinases (SFKs) and Syk that leads to downstream Erk and Akt activation and the macrophage anti-microbial response. To minimize local tissue damage in the absence of a true pathogenic threat, macrophages must remain unresponsive to low-valency receptor ligation by soluble ligands from food or remote infection sites. To investigate how SFKs regulate macrophage sensitivity, we compared signaling in murine bone-marrow-derived macrophages (BMDMs) exposed to depleted zymosan, a particulate and highly multivalent Dectin-1 ligand, with signaling after pharmacologically induced SFK activation without receptor engagement or formation of a phagocytic synapse. We show that high-valency Dectin-1 engagement and formation of a phagocytic synapse restrict phosphorylation of the ITIM-associated phosphatase SHIP1 and promote Erk and Akt signaling. In contrast, SFK activation in the absence of a phagocytic synapse induces phosphorylation of SHIP1 and leads to dampened activation of Erk and Akt. Whereas multiple SFKs are capable of phos-phorylating SHIP1 in principle, the SFK Lyn functions uniquely in maintaining steady-state phosphorylation of SHIP1 and setting tonic and induced levels of Erk and Akt phosphorylation. Consequently, Lyn has a special role in suppressing the Akt pathway and maintaining Erk/Akt pathway balance. Interestingly, formation of a phagocytic synapse circumvents this requirement for Lyn to maintain Erk/Akt balance. These findings highlight the unique function of Lyn in maintaining mac-rophage steady-state signaling and limiting pro-inflammatory responses to disorganized pathway activation and soluble microbial components.

  PublisherOA PDFDOI

• Discovery Stack Pilot: Feasibility and Outcomes of a Scientist-Designed Peer Review Model Separating Quality and Impact

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-02

  preprintOpen access

  ABSTRACT Peer review serves as the cornerstone of scientific quality control. Yet, the current journal-centric system is hindered by long timelines, high publication costs, inconsistent review quality, systemic biases, and editorial gatekeeping. Notably, the system is built around misaligned measures of impact that are tethered to journal branding and conflate scientific rigor ( Quality ) with perceived significance ( Impact ). Here, we report findings from the Discovery Stack Pilot Study, which tested a scientist-designed, journal-independent peer review model. The Discovery Stack model integrates in-line reviewer comments to promote constructive, improvement-focused feedback and generates separate, multimodal assessments of scientific Quality and Impact . To examine its feasibility and effectiveness, manuscripts enrolled in the pilot were reviewed in parallel with traditional journal review. A total of 162 reviews were completed, and survey data from 86 participants were analyzed to evaluate the experience of both authors and reviewers. The results showed that reviewers effectively evaluated Quality and Impact as separate dimensions, with Quality scores being more consistent across reviewers than Impact scores. Importantly, participants strongly supported the core elements of the Discovery Stack model and expressed enthusiasm for its broader adoption to enhance transparency, efficiency, and value in peer review. Future studies will explore integrating this model into a digital platform for reviewing and curating scientific discoveries to improve the production and dissemination of high-quality research.

  PublisherOA PDFDOI

• Total, not isoform-specific, Lyn expression by macrophages promotes TLR activation and restricts proliferation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-10

  preprintOpen accessSenior authorCorresponding

  Abstract Toll-like receptor (TLR) signaling is vital to antimicrobial macrophage function, and its dysregulation is associated with many disease states, including lupus, multiple sclerosis, pulmonary fibrosis, and cancer. The Src-family kinase Lyn plays activating and inhibitory roles downstream of TLRs, yet distinct functions of the Lyn splice variants LynA and LynB in TLR signaling had not been investigated. We used isoform-specific Lyn knockout mice (LynA KO and LynB KO ) to interrogate the contribution of each isoform to TLR signaling in bone marrow-derived macrophages. Bulk RNA sequencing and cytokine analyses revealed that complete Lyn deficiency (Lyn KO ) dampens TLR4- and TLR7-induced inflammatory gene expression and TNF production, but enhances the expression of genes responsible for synthesizing the extracellular matrix and promoting proliferation. Despite a reduction in total Lyn levels, the expression of either LynA or LynB alone was sufficient to preserve wild-type transcriptional responses and TNF production in response to the TLR7 agonist R848. However, LyA KO and LynB KO macrophages did have partially impaired TNF production in response to the TLR4 agonist lipopolysaccharide. Additionally, LynA KO and LynB KO macrophages were hyperproliferative, like Lyn KO cells. These data suggest that Lyn promotes macrophage activation downstream of TLRs and restrains aberrant proliferation and matrix deposition in a dose-dependent rather than isoform-specific manner. Summary Sentence RNA sequencing and functional assays demonstrate that both LynA and LynB restrict macrophage proliferation and drive TLR-induced ECM-remodeling and inflammatory cytokine production.

  PublisherOA PDFDOI

• Lyn Kinase Regulates Myeloid-Cell Responses to Mammary Tumors 2752

  The Journal of Immunology · 2025-11-01

  articleOpen accessSenior author

  Abstract Description Myeloid-cell enrichment in tumors is correlated with increased metastasis, reduced survival times, and poor treatment outcomes in breast cancer. Many signals (CSF, Il-6, chemokine) to myeloid cells in the tumor microenvironment are transduced through the Src-family kinase Lyn, which is expressed as two isoforms: LynA and LynB. Total Lyn expression is negatively correlated with breast cancer patient survival, but the functional contributions of LynA and LynB in solid tumors have not been studied. In an E0771 orthotopic transplant model in hosts expressing or lacking LynA or LynB, we have discovered that Lyn expression in the mammary tumor microenvironment promotes the early recruitment of monocytes, macrophages, neutrophils, and dendritic cells, as determined by flow cytometry analysis of tumors early in development. Furthermore, Lyn promotes anti-inflammatory activation of tumor-associated macrophages. Tumors from Lyn knockout animals maintained WT-like numbers of inflammatory, anti-tumor macrophages, but the anti-inflammatory population was reduced. Together, our findings suggest that Lyn regulates the tumor-mediated chemotactic and inflammatory signaling response of myeloid cells, which are major factors in disease progression and treatment response. Modulation of Lyn activity, or the activity of its downstream signaling partners, is thus a potential strategy for manipulating the trafficking and anti-tumor activity of myeloid cells within breast tumors to benefit patients. Funding Sources Supported by American Cancer Society Kirby Foundation Postdoctoral Fellowship PF-21-068-01-LIB and NIH/NCI T32 CA009138. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

  PublisherOA PDFDOI

• Lyn expression in macrophages promotes TLR activation and restricts proliferation in an isoform-independent manner

  Journal of Leukocyte Biology · 2025-10-04 · 2 citations

  articleOpen accessSenior author

  Toll-like receptor (TLR) signaling is vital for antimicrobial macrophage function, and its dysregulation is associated with diseases such as lupus, multiple sclerosis, pulmonary fibrosis, and cancer. The Src-family kinase Lyn may have net activating or inhibitory effects on TLR signaling, yet distinct functions of the Lyn splice variants LynA and LynB in TLR signaling have not been investigated. We used isoform-specific Lyn knockout mice (LynAKO and LynBKO) to interrogate the contribution of each isoform to TLR signaling in bone-marrow-derived macrophages. Bulk RNA sequencing and cytokine analyses revealed that complete Lyn deficiency (LynKO) dampened TLR4- and TLR7-induced inflammatory gene expression and production of tumor necrosis factor but enhanced the expression of genes responsible for synthesizing the extracellular matrix and promoting proliferation. Despite reduced expression of total Lyn in single-isoform-knockout bone-marrow-derived macrophages, expression of either LynA or LynB alone was sufficient to preserve a wild-type-like transcriptome at steady state and after treatment with the TLR7 agonist R848. However, LynAKO and LynBKO macrophages did have impaired production of tumor necrosis factor in response to the TLR4 agonist lipopolysaccharide. Additionally, LynAKO and LynBKO macrophages were as hyperproliferative as LynKO cells. These data suggest that Lyn promotes macrophage activation in response to TLR signaling and restrains aberrant proliferation and matrix deposition in a dose-dependent rather than isoform-specific manner.

  PublisherDOI

• Allosteric coupling asymmetry mediates paradoxical activation of BRAF by type II inhibitors

  eLife · 2024-04-03

  preprintOpen access

  Abstract The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction of BRAF dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking BRAF dimerization and conformation we built an allosteric model of inhibitor-induced dimerization that resolves the allosteric contributions of inhibitor binding to the two active sites of the dimer, revealing key differences between type I and type II RAF inhibitors. For type II inhibitors the allosteric coupling between inhibitor binding and BRAF dimerization is distributed asymmetrically across the two dimer binding sites, with binding to the first site dominating the allostery. This asymmetry results in efficient and selective induction of dimers with one inhibited and one catalytically active subunit. Our allosteric models quantitatively account for paradoxical activation data measured for 11 RAF inhibitors. Unlike type II inhibitors, type I inhibitors lack allosteric asymmetry and do not activate BRAF homodimers. Finally, NMR data reveal that BRAF homodimers are dynamically asymmetric with only one of the subunits locked in the active αC-in state. This provides a structural mechanism for how binding of only a single αC-in inhibitor molecule can induce potent BRAF dimerization and activation.

  PublisherDOI

• Author response: Allosteric coupling asymmetry mediates paradoxical activation of BRAF by type II inhibitors

  2024-05-14

  peer-reviewOpen access

  A comprehensive allosteric model describes how inhibitors can activate rather than inhibit a target kinase by selectively driving formation of kinase dimers with one inhibited and one activated subunit.

  PublisherDOI

• Author response: Allosteric coupling asymmetry mediates paradoxical activation of BRAF by type II inhibitors

  2024-04-03

  peer-reviewOpen access

  The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction of BRAF dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking BRAF dimerization and conformation we built an allosteric model of inhibitor-induced dimerization that resolves the allosteric contributions of inhibitor binding to the two active sites of the dimer, revealing key differences between type I and type II RAF inhibitors. For type II inhibitors the allosteric coupling between inhibitor binding and BRAF dimerization is distributed asymmetrically across the two dimer binding sites, with binding to the first site dominating the allostery. This asymmetry results in efficient and selective induction of dimers with one inhibited and one catalytically active subunit. Our allosteric models quantitatively account for paradoxical activation data measured for 11 RAF inhibitors. Unlike type II inhibitors, type I inhibitors lack allosteric asymmetry and do not activate BRAF homodimers. Finally, NMR data reveal that BRAF homodimers are dynamically asymmetric with only one of the subunits locked in the active αC-in state. This provides a structural mechanism for how binding of only a single αC-in inhibitor molecule can induce potent BRAF dimerization and activation.

  PublisherDOI

Recent grants

• Generating LynA-/- and LynB-/- mice by CRISPR/Cas9 genome editing

  NIH · $153k · 2017–2018

• NIH Grant F32AI082926

  NIH · $102k · 2011

• Roles of the Src-Family Kinases LynA and LynB in Macrophage Inflammatory Signaling

  NIH · $2.2M · 2018–2025

Frequent coauthors

• J.T. Greene

  University of Minnesota

  32 shared

• Ben F. Brian

  21 shared

• Justin M. Drake

  14 shared

• Justin H. Hwang

  Twin Cities Orthopedics

  13 shared

• Arthur Weiss

  12 shared

• John Kuriyan

  Vanderbilt University

  12 shared

• Hannah E. Bergom

  10 shared

• Song Yi Bae

  10 shared

Labs

• Tanya Freedman LabPI

Education

• Postdoctoral, Medicine/Rheumatology

  University of California

  2014

• Ph.D., Molecular and Cell Biology

  University of California

  2007

• A.B., Biochemistry

  Bowdoin College

  1999