Innate and adaptive immune functions are governed by instructive signals from receptors that sense pathogens and toxins. Ligation of lymphocyte antigen receptors triggers a series of characteristic events that is initiated by activation of Src family tyrosine kinases followed by recruitment and activation of Syk and BTK family nonreceptor tyrosine kinases (18). The ensuing tyrosine phosphorylation provides docking sites for SH2 and PTB domains on adaptor proteins and enzymes, which assemble into a spatially highly defined complex that will ultimately cause lymphocyte activation. For instance, in T cells, the adaptor proteins SLP-76 and Gads (Grb2-related adaptor downstream of Shc) are recruited to the transmembranous adaptor LAT, forming a central scaffold for the activation of several effector molecules, such as phospholipase C␥ (PLC␥), Ras, and Rho GTPases (15). These events are followed by the activation of a number of different serine/threonine kinases, which include members of the protein kinase B (PKB), PKC, and PKD families as well as mitogen-activated protein 3 (MAP3) and MAP4 kinases, such as mitogen-activated protein kinase kinase kinase 1 (MEKK1) and hematopoietic progenitor kinase 1 (HPK1). Further downstream, mitogen-activated protein kinases (MAPKs) which contribute to the immune response are efficiently triggered; for instance, stress-activated protein kinases (SAPKs)/c-Jun N-terminal kinases (JNKs) have been shown to regulate critical steps in T-helper-cell differentiation (8). Transcription factors of the NF-B family constitute an additional major pathway involved in the regulation of lymphocytes and execution of immune functions. NF-B transcription factors determine life and death decisions in developing lymphocytes and also provide important costimulatory signals in T cells (16).Lymphocyte receptor signaling can be coupled to SAPK/ JNK and NF-B activation by HPK1 (18). HPK1 is a mammalian hematopoiesis-specific Ste20 homologue belonging to the germinal center (GC) kinase family, which contains at least 20 kinases (6). HPK1 is characterized by an N-terminal kinase domain, followed by an intermediate region and a C-terminal Citron homology domain. Both the N-terminal kinase domain and the C-terminal Citron homology domain are highly conserved among related kinases of the GC family. In the GC family, HPK1 is most closely related to germinal center kinase (GCK), germinal center-like kinase (GLK), and germinal center-related kinase (GCKR), which together form subfamily I of GCKs (19). The biological function of these Ste20 homologues is largely elusive. GCK and GCKR have been implicated in tumor necrosis factor receptor signaling (36, 42). More recently, HPK1 has been shown to be a positive regulator of cell death in T cells (35).HPK1 has been demonstrated to be a potent and highly specific activator of the SAPKs/JNKs in various cell types, a property shared with the related GCK family members (18,19). HPK1 likely acts at the level of a MAP4 kinase, resulting in the activation of MAP3 kinases, such...

Lymphatic vessels are essential for tissue homeostasis and immune surveillance and contribute to pathological conditions. Lymphatic endothelium differentiates from veins and forms an independent vascular tree with only few connections to the venous circulation. Failure of blood and lymphatic vessel separation results in hemorrhage and edema. VEGF-C and -D are strong inducers of lymphangiogenesis and have essential (VEGF-C) and modulatory (VEGF-D) roles during developmental lymphangiogenesis. We describe here a myeloid population that is defined by expression of the tyrosine kinase Syk, comprises largely M2-polarized mononuclear cells, and robustly expresses angiogenic factors, including VEGF-C/-D and chemokines. These cells stimulate lymphangiogenesis in vivo. Deletion of Syk causes increased chemotractant production, enhanced transmigration, and accumulation in the skin. Ensuing lymphatic hyperplasia and vessel dilation cause the formation of blood-lymphatic shunts. This mechanism does not involve circulating endothelial progenitor cells and demonstrates the potential of hematopoietic cells to control developmental lymphangiogenesis.

The non-receptor tyrosine kinase Syk is a well-characterized hematopoietic signal transducer, which is also expressed in non-hematopoietic cells. In epithelial cells, the function of Syk is not wholly known. It interacts with the receptor tyrosine kinase DDR1 and is frequently lost from metastatic mammary tumors. Here, using genetic tracing, we demonstrate Syk expression in murine mammary epithelium, myoepithelium and skin epithelium, but not in intestinal or lung epithelia. Investigating possible functions of Syk, we found a substantial suppression of cell mobility that depended on Syk kinase activity in trans-well migration and wounding assays. Co-expression of DDR1 resulted in constitutive interaction and strong activation of Syk kinase. Most importantly, Syk-mediated migration inhibition was blocked in the presence of DDR1, while conversely DDR1 knockdown restored migration inhibition. Our study identifies Syk as a potent inhibitor of epithelial migration and describes a first functional consequence of the interaction with the collagen receptor DDR1.

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Ulcerative dermatitis (UD) is a severe inflammatory skin disorder with an unknown aetiology. Recently, insulin receptor substrate 1 KO mice were shown to be fully resistant to UD. In this study, we showed that high-fat diet (HFD) feeding significantly increased incidence of UD in wild type (WT) C57BL/6 mice, as did lithium-mediated inhibition of GSK3-b, which is a key negative regulator of IRS1. In contrast to WT mice, resistance to UD was fully preserved in HFD-fed Irs1-KO mice. Our results identify IRS1 as a key determinant of UD pathogenesis and establish a direct link between diet composition, obesity-induced inflammation and chronic ulceration.