The Signal Transduction Laboratory is studying signaling pathways that play a role in immune system development and function. We are primarily interested in what regulates hematopoiesis or blood cell development, and believe that this will give us a greater understanding of the signals that go awry in the development of blood cell cancers. We are also interested in understanding what regulates the development of immunity and we are trying to understand the processes that are perturbed when autoimmunity and inflammatory diseases develop.

We have been concentrating our studies on Src-family protein tyrosine kinases, enzymes that are found inside cells that play very important roles in transmitting information from the cell surface to the nucleus to initiate a cellular response. Deregulation of the function of Src-family kinases has been linked with cancer, and also to immune system disorders such as autoimmune disease, immunodeficiency, osteopetrosis, and compromised host defence. The Lyn tyrosine kinase is a unique member of the Src-family whose predominant role is to regulate signals through inhibitory receptors, and to promote signal termination.

Animal models of Lyn deficiency and constitutive Lyn activity have been developed in the laboratory and are the major focus of our studies. Our studies have demonstrated the importance of Lyn for B lymphocyte development and function, and have identified Lyn as a potential tumour suppressor: mice deficient in Lyn develop myeloid tumours, whereas mice expressing a constitutively active form of Lyn show no predisposition towards tumour development.

We have also found that Lyn plays a critical role in Th1 and Th2 immune responses and in dendritic cell maturation and function. Our research employs a variety of powerful techniques such as mouse models, mutagenesis, four-colour flow cytometry, RNA interference, real-time PCR, proteomics and micro-array based RNA expression analysis.

1. Analyzing the interaction between the Src-family kinase Lyn and the inositol phosphatase SHIP-1. Recent studies have suggested that Lyn operates in part by regulating some aspects of SHIP-1 function. Lyn-deficient mice show loss of negative regulation of SHIP-1 and amplification of signaling pathways that are coordinated by PI3K. We are now assessing the genetic interaction of Lyn and SHIP-1 through mice simultaneously deficient in both enzymes.

2. Identifying Lyn-regulated proteins and genes. We are attempting to identify Lyn regulated proteins and genes using proteomics and microarray technologies. For these studies we are making use of cells from mice expressing a gain of function mutation in Lyn, as they show numerous tyrosine phosphorylated proteins that are likely to be bone fide Lyn substrates.

3. Investigating the role of Lyn in innate immune responses. We have found that Lyn plays an important role in dendritic cell maturation and function, and have found that through its role in dendritic cells, Lyn orchestrates the response of mice to Th1 and Th2 immune challenges. Our current studies are aimed at identifying the biochemical basis for the alteration in dendritic cell maturation and function.

4. Understanding the role of Lyn in human leukemia. Recent studies have implicated Lyn in human leukemias, with studies suggesting that activation of Lyn may be particularly important in promoting tumour growth. We have recently joined forces with investigators at the Peter MacCallum Cancer Centre to assess the efficacy of Src family kinase inhibitors on patients with leukemia.

5. Determining how Lyn regulates haematopoiesis and progenitor cell number. Our previous studies have shown that Lyn deficiency leads to deregulation of hematopoiesis and increases in progenitor cell numbers. We are actively investigating the basis for these phenotypes.

6. Defining the role of Lyn in inflammatory lung disease and cancer. We have previously shown that Lyn functions as a negative regulator of lung inflammation. However, we have also found that Lyn can be a positive regulator of signaling: mice expressing a gain of function mutation in Lyn develop destructive lung inflammation. We are now trying to understand how Lyn activation contributes to macrophage deregulation and chronic obstructive pulmonary disease, and whether mutation of Lyn alters susceptibility to lung adenocarcinoma.

Hibbs ML, Tarlinton DM, Armes J, Grail D, Hodgson G, Maglitto R, Stacker SA and Dunn AR. Multiple defects in the immune system of lyn-deficient mice, culminating in autoimmune disease. Cell. 83: 301-311, 1995.

Harder KW, Parsons LM, Armes J, Evans N, Kountouri N, Clark R, Quilici C, Grail D, Hodgson GS, Dunn AR, and Hibbs ML. Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage. Immunity. 15: 603-615, 2001.

Hibbs ML, Harder, KW, Armes J, Kountouri N, Quilici C, Casagranda F, Dunn AR, and Tarlinton DM. Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity. J. Exp. Med. 196: 1593-1604, 2002.

Harder KW, Quilici C, Naik E, Inglese M, Kountouri N, Turner A, Zlatic K, Tarlinton DM and Hibbs ML. Perturbed myelo/erythropoiesis in Lyn-deficient mice is similar to that in mice lacking the inhibitory phosphatases SHP-1 and SHIP-1. Blood, 104: 3901-3910, 2004.

Beavitt S-JE, Harder KW, Kemp JM, Jones J, Quilici C, Casagranda F, Lam E, Turner D, Brennan S, Sly PD, Tarlinton DM, Anderson GP and Hibbs ML.  Lyn-deficient mice develop severe, persistent asthma: a critical role for Lyn as a negative regulator of Th2 immunity.  J. Immunol. 175: 1867-1875, 2005.

Xu Y, Harder KW, Huntington ND, Hibbs ML and Tarlinton DM.  Lyn tyrosine kinase; accentuating the positive and the negative.  Immunity, 22: 9-18, 2005.

Hibbs ML and Harder KW.  The duplicitous nature of the Lyn tyrosine kinase in growth factor signaling.  Growth Factors 24: 137-149, 2006.