A role for Lyn kinase as a positive regulator of immunoglobulin (Ig)E-dependent allergy has long been accepted. Contrary to this belief, Lyn kinase was found to have an important role as a negative regulator of the allergic response. This became apparent from the hyperresponsive degranulation of lyn − / − bone marrow–derived mast cells, which is driven by hyperactivation of Fyn kinase that occurs, in part, through the loss of negative regulation by COOH-terminal Src kinase (Csk) and the adaptor, Csk-binding protein. This phenotype is recapitulated in vivo as young lyn − / − mice showed an enhanced anaphylactic response. In vivo studies also demonstrated that as lyn − / − mice aged, their serum IgE increased as well as occupancy of the high affinity IgE receptor (FcεRI). This was mirrored by increased circulating histamine, increased mast cell numbers, increased cell surface expression of the high affinity IgE receptor (FcεRI), and eosinophilia. The increased IgE production was not a consequence of increased Fyn kinase activity in lyn − / − mice because both lyn − / − and lyn − / − fyn − / − mice showed high IgE levels. Thus, lyn − / − mice and mast cells thereof show multiple allergy-associated traits, causing reconsideration of the possible efficacy in therapeutic targeting of Lyn in allergic disease.

To investigate the role of the Lyn kinase in establishing signaling thresholds in hematopoietic cells, a gain-of-function mutation analogous to the Src Y527F-activating mutation was introduced into the Lyn gene. Intriguingly, although Lyn is widely expressed within the hematopoietic system, these mice displayed no propensity toward hematological malignancy. By contrast, analysis of aging cohorts of both loss- and gain-of-function Lyn mutant mice revealed that Lyn(-/-) mice develop splenomegaly, increased numbers of myeloid progenitors, and monocyte/macrophage (M phi) tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells. Loss of such inhibitory signaling may predispose mice lacking this putative protooncogene to tumorigenesis.

Lyn, one of several Src-family tyrosine kinases in immune cells, is noted for its ability to negatively regulate signaling pathways through phosphorylation of inhibitory receptors, enzymes, and adaptors. Somewhat paradoxically, it is also a key mediator in several pathways of B cell activation, such as CD19 and CD180. Whether Lyn functions to promote or inhibit immune cell activation depends on the stimulus and the developmental state, meaning that the consequences of Lyn activity are context dependent. The importance of regulating Lyn activity is exemplified by the pathological conditions that develop in both lyn-/- and lyn gain-of-function mice (lynup/up), including lethal antibody-mediated autoimmune diseases and myeloid neoplasia. Here, we review the outcomes of altered Lyn activity within the framework of B cell development and differentiation and the circumstances that appear to dictate the outcome.

The type III transforming growth factor ␤ (TGF␤) receptor (T␤RIII) binds both TGF␤ and inhibin with high affinity and modulates the association of these ligands with their signaling receptors. However, the significance of T␤RIII signaling in vivo is not known. In this study, we have sought to determine the role of T␤RIII during development. We identified the predominant expression sites of ⌻␤RIII mRNA as liver and heart during midgestation and have disrupted the murine T␤RIII gene by homologous recombination. Beginning at embryonic day 13.5, mice with mutations in ⌻␤RIII developed lethal proliferative defects in heart and apoptosis in liver, indicating that T␤RIII is required during murine somatic development. To assess the effects of the absence of T␤RIII on the function of its ligands, primary fibroblasts were generated from T␤RIII-null and wild-type embryos. Our results indicate that T␤RIII deficiency differentially affects the activities of TGF␤ ligands. Notably, T␤RIII-null cells exhibited significantly reduced sensitivity to TGF␤2 in terms of growth inhibition, reporter gene activation, and Smad2 nuclear localization, effects not observed with other ligands. These data indicate that T␤RIII is an important modulator of TGF␤2 function in embryonic fibroblasts and that reduced sensitivity to TGF␤2 may underlie aspects of the T␤RIII mutant phenotype.Members of the transforming growth factor ␤ (TGF␤) family are potent regulators of multiple cellular functions, including cell proliferation, differentiation, migration, and death (35, 64). As such, the TGF␤s are critical regulators of the growth and morphogenesis of a variety of tissues. Three TGF␤ isoforms (TGF␤1 to -3) have been described in mammals and are encoded by distinct genes (36). Although the three ligands have similar biological activities in many in vitro assays, null mutations in the three genes result in mice with distinct phenotypes, suggesting that each ligand has a unique role during murine somatic development (14,42,50). In mammalian cells, the diverse actions of the TGF␤s are mediated by two distinct type I and type II serine/threonine kinase receptors (T␤RI and T␤RII, respectively), which are expressed on most cell types and tissues (35). T␤RI and T␤RII can form a latent receptor complex, and ligand binding is required for the activation of the receptor complex (65). Upon TGF␤ binding, the receptors rotate relatively within the complex (65, 66), resulting in phosphorylation and activation of T␤RI by the constitutively active and autophosphorylated T␤RII (62). The activated T␤RI then directly signals to downstream intracellular substrates, e.g., Smads (21, 61).Many other cell surface receptors have been identified (64). Among them is the type III TGF␤ receptor T␤RIII, which binds to all three TGF␤s (32). In contrast to the type I and II receptors, T␤RIII, also known as betaglycan, appears dispensable for TGF␤-mediated signal transduction since most cells that lack functional T␤RIII still respond to TGF␤ (8). The murine form of T␤RIII is an 850-...