Functions of the Lyn tyrosine kinase in health and disease

Abstract

Src family kinases such as Lyn are important signaling intermediaries, relaying and modulating different inputs to regulate various outputs, such as proliferation, differentiation, apoptosis, migration and metabolism. Intriguingly, Lyn can mediate both positive and negative signaling processes within the same or different cellular contexts. This duality is exemplified by the B-cell defect in Lyn−/− mice in which Lyn is essential for negative regulation of the B-cell receptor; conversely, B-cells expressing a dominant active mutant of Lyn (Lynup/up) have elevated activities of positive regulators of the B-cell receptor due to this hyperactive kinase. Lyn has well-established functions in most haematopoietic cells, viz. progenitors via influencing c-kit signaling, through to mature cell receptor/integrin signaling, e.g. erythrocytes, platelets, mast cells and macrophages. Consequently, there is an important role for this kinase in regulating hematopoietic abnormalities. Lyn is an important regulator of autoimmune diseases such as asthma and psoriasis, due to its profound ability to influence immune cell signaling. Lyn has also been found to be important for maintaining the leukemic phenotype of many different liquid cancers including acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and B-cell lymphocytic leukaemia (BCLL). Lyn is also expressed in some solid tumors and here too it is establishing itself as a potential therapeutic target for prostate, glioblastoma, colon and more aggressive subtypes of breast cancer.Lay AbstractTo relay information, a cell uses enzymes that put molecular markers on specific proteins so they interact with other proteins or move to specific parts of the cell to have particular functions. A protein called Lyn is one of these enzymes that regulate information transfer within cells to modulate cell growth, survival and movement. Depending on which type of cell and the source of the information input, Lyn can positively or negatively regulate the information output. This ability of Lyn to be able to both turn on and turn off the relay of information inside cells makes it difficult to fully understand its precise function in each specific circumstance. Lyn has important functions for cells involved in blood development, including different while blood cells as well as red blood cells, and in particular for the immune cells that produce antibodies (B-cells), as exemplified by the major B-cell abnormalities that mice with mutations in the Lyn gene display. Certain types of leukaemia and lymphoma appear to have too much Lyn activity that in part causes the characteristics of these diseases, suggesting it may be a good target to develop new anti-leukaemia drugs. Furthermore, some specific types, and even specific subtypes, of solid cancers, e.g. prostate, brain and breast cancer can also have abnormal regulation of Lyn. Consequently, targeting this protein in these cancers could also prove to be beneficial.

A PrPC-caveolin-Lyn complex negatively controls neuronal GSK3β and serotonin 1B receptor

“…A good candidate alternative to Fyn for relaying the inactivation of GSK3β is Lyn, another src kinase, which partitions with PrP C in rafts of neuronal cells16. The level of pY507-Lyn, which corresponds to inactivated Lyn17, did not vary when 1C11 5-HT neuronal cells were exposed to the C-terminal SAF61 antibody (Fig. 3b).…”

Thymidine Phosphorylase Participates in Platelet Signaling and Promotes Thrombosis

“…Lyn is a major SFK in human and mouse platelets, and plays important and complex roles in platelet activation 22 . All SFKs contain aSH3 domain that serves as a site for protein interactions by binding to proline-rich peptide sequences in its binding partners 23 . We analyzed the sequence of human TYMP and discovered a consensus SH3-binding sequence APPAP 24 at the N-terminus of TYMP (Figure 3A), which is highly conserved in different primate species.…”

An indoxyl compound 5-bromo-4-chloro-3-indolyl 1,3-diacetate, CAC-0982, suppresses activation of Fyn kinase in mast cells and IgE-mediated allergic responses in mice

“…The cross-linking of antigen-stimulated receptors activates the Src-family kinase, such as Lyn, Fyn, Fgr, and downstream signaling molecules such as Syk, LAT, SLP-76, PLD2, and PLCγ Gilfillan, 2006: Lee et al, 2011). Although the Lyn-dependent pathway leads to the initial activation of FcεRI proximal signals in mast cells, it involves also negative signaling processes in the cells to maintain its homeostasis (Roth et al, 2008;Ingley, 2012). On the other hand, Fyn kinase shows largely a positive regulatory role for the induction of degranulation, synthesis and release of leukotrienes, and the production of cytokines via the Gab2/PI3K pathway (Gomez et al, 2005;Parravicini et al, 2002) and/or Syk (Yu et al, 2006).…”