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 To 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.

Figure 1

Regulation of Lyn and Lyn pathways.A) Domain architecture of Lyn. Schematic of Lyn protein functional domains and motifs, unique (UN), Src Homology 3 (SH3), Src Homology 2 (SH2), and Kinase domains, proline motif in the hinge region (P), amino terminal lipid modifications are indicated; myristoylation (navy blue) and palmitoylation (cyan). Important pY motifs that are phosphorylated in the inactive (pY508, red) and active (pY397, green) kinase are indicated, as is the LynA/p56 isoform-specific motif pY32 that may modulate activity/interactions. Intramolecular interactions between the SH3 domain and the hinge (P) region, as well as the SH2 domain and the C-terminal pY508 motif are shown. B) Lyn regulation of positive and negative signaling pathways. Lyn regulates multiple signaling pathways by interacting with and/or phosphorylating different molecules that can mediate both the activation/enhancement as well as the inhibition/termination of signaling networks, as illustrated.

Figure 2

Mutations of Lyn in genetically engineered mice.A) Deletion of exon 1 in Lyn^−/− mice. Schematic of the genomic region of Lyn highlighting the generation of Lyn^−/− mice through the replacement of exon one and surrounding sequences with a PGK-Neo cassette, transcribed in the opposite orientation to the Lyn gene. B) Lyn^up/up mice contain a point mutation of the C-terminal tyrosine, generating a phenylalanine (Y508F) that is unable to be phosphorylated. C) Lyn^Mld4/Mld4 mice contain a point mutation of a threonine at the end of the activation look, to a lysine (T410K), which inhibits the activity of the enzyme. D) WeeB mice contain a point mutation in the glycine loop, a glutamic acid is changed to a glycine (E260G), inhibiting binding of Mg-ATP, resulting in an inactive enzyme. E) The Tel-Lyn fusion juxtaposes the PNT domain of Tel (ETV6) with a truncated Lyn lacking its regulatory UN/SH3/SH2 domains, generating a constitutively active kinase fusion. Domains and motifs of Lyn are as described in Figure 1.