|Coordinate||3,789,908 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||LYN proto-oncogene, Src family tyrosine kinase|
|Chromosomal Location||3,678,115-3,813,122 bp (+)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a tyrosine protein kinase, which maybe involved in the regulation of mast cell degranulation, and erythroid differentiation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2011]
PHENOTYPE: Homozygotes for targeted null mutations exhibit splenomegaly, reduced numbers of peripheral B cells, impaired immune responses, IgM hyperglobulinemia, autoimmunity with glomerulonephritis, and monocyte/macrophage tumors. [provided by MGI curators]
|Amino Acid Change||Tyrosine changed to Stop codon|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000038838] [ENSMUSP00000100075]|
Lyn Tyrosine Kinase Domain, apo form [X-RAY DIFFRACTION]
Lyn Tyrosine Kinase Domain-AMP-PNP complex [X-RAY DIFFRACTION]
Lyn Tyrosine Kinase Domain-PP2 complex [X-RAY DIFFRACTION]
Lyn Tyrosine Kinase Domain-Dasatinib complex [X-RAY DIFFRACTION]
Structure of unliganded Lyn SH2 domain [X-RAY DIFFRACTION]
AA Change: Y501*
|Predicted Effect||probably null|
AA Change: Y480*
|Predicted Effect||probably null|
|Meta Mutation Damage Score||0.9755|
|Is this an essential gene?||Non Essential (E-score: 0.000)|
|Candidate Explorer Status||CE: excellent candidate; Verification probability: 0.969; ML prob: 0.956; human score: 4.5|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Semidominant|
|Last Updated||2019-09-04 9:47 PM by Diantha La Vine|
|Record Created||2014-12-18 12:06 AM by Jin Huk Choi|
The Cress phenotype was identified among N-Nitroso-N-ethylurea (ENU)-mutagenized G3 mice of the pedigree R1460, some of which showed a reduced B to T cell ratio (Figure 1) due to a reduced frequency of total B cells (Figure 2), an increased frequency of B1a cells (Figure 3), an increased frequency of B1a cells in B1 cells (Figure 4), a reduced frequency of IgM+ B cells (Figure 5), and a reduced percentage of IgD+ B cells (Figure 6) with a concomitant increased frequency of T cells (Figure 7) including both CD4+ T cells (Figure 8) and CD8+ T cells (Figure 9), all in the peripheral blood. Some mice also exhibited a reduced B220 mean fluorescence intensity on B cells in the peripheral blood (Figure 10). Some mice showed a diminished T-dependent antibody response to ovalbumin administered with aluminum hydroxide (OVA/Alum) (Figure 11), a diminished T-dependent response to recombinant Semliki Forest virus (rSFV)-encoded β-galactosidase (rSFV-β-gal) (Figure 12), and a diminished T-independent antibody response to 4-hydroxy-3-nitrophenylacetyl-Ficoll (NP-Ficoll) (Figure 13).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 96 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Lyn: a T to A transversion at base pair 3,789,908 (v38) on chromosome 4, or base pair 111,788 in the GenBank genomic region NC_000070. The strongest association was found with an additive model of linkage to the normalized peripheral IgD+ B cell percentage, wherein three variant homozygotes and eight heterozygotes departed phenotypically from five homozygous reference mice with a P value of 1.583 x 10-8 (Figure 14). A dominant effect was observed for the T-independent B cell response to NP-Ficoll as well as the frequency of B1a cells in B1 cells; a recessive effect was observed for the T-dependent antibody response to OVA/Alum. The mutation corresponds to residue 1,752 in the mRNA sequence NM_001111096 within exon 13 of 13 total exons and residue 1,689 in the mRNA sequence NM_010747 within exon 13 of 13 total exons.
Genomic numbering corresponds to NC_000070. The mutated nucleotide is indicated in red. Alternative splicing of exon 2 of Lyn produces two Lyn isoforms, Lynp56 and Lynp53, that differ at the N-terminus (1;2); Lynp56 contains an additional 21 amino acids compared to Lynp53 (1). The mutation results in substitution of tyrosine 501 (Tyr501) for a premature stop codon (Tyr501*) in the Lynp56 protein and a Tyr480* in the Lynp53 protein.
|Illustration of Mutations in
Gene & Protein
Lyn is a member of the Src family of tyrosine kinases (SFKs) which also includes Src, Yes, Fgr, Fyn, Lck (see the record for iconoclast), Hck, Blk, and Yrk. The members of the SFKs share highly conserved domains including a Src-homology 3 (SH3) domain (amino acids 66-122 in Lyn), an SH2 domain (amino acids 127-217), a tyrosine kinase domain (amino acids 247-497), and a C-terminal regulatory region [Figure 15; reviewed in (1-3)]. A ‘unique’ domain of 50-70 amino acids between the N-terminus and the SH3 domain varies among the members of the SFKs (3). The function of the unique domain in Lyn is unknown; in Lck it mediates protein-protein interactions between Lck and the cytoplasmic tails of the T-cell coreceptors CD4 and CD8 (4;5). The Cress mutation (Tyr501*) occurs in the undefined region following the kinase domain in both Lyn isoforms. No functions have been attributed to this region.
Please see the record Lemon for information about Lyn.
Lyn can act as both a positive and negative signaling molecule in several cell types including hematopoietic progenitors, mature myeloid cells (neutrophils, macrophages, monocytes, eosinophils, and dendritic cells), platelets, erythrocytes, and osteoclasts. As a result, Lyn regulates several cellular functions including proliferation, degranulation, cytokine production, adhesion, activation, migration, and survival. Following BCR ligation, Lyn phosphorylates the immunoreceptor tyrosine-based activation motifs (ITAMs) of the Igα/Igβ BCR subunits (6-8). These signals allow the activation of multiple transcription factors, including nuclear factor of activated T cells (NF-AT), NF-κB (see the records for Finlay and xander) and AP-1, which subsequently regulate biological responses including cell proliferation, differentiation, and apoptosis as well as the secretion of antigen-specific antibodies [reviewed in (9)]. Lyn has a non-redundant role in negative regulation of BCR signaling (6). Lyn phosphorylates the ITIMs of the BCR associated co-receptors CD22 (see the record for well), Fc receptor gamma IIb (FcγRIIb), and paired immunoglobulin-like receptor-B (PIR-B) (10-15).
Lyn-/- mice exhibit progressive splenomegaly and enlargement of lymph nodes, reduced numbers of mature follicular B cells, absence of marginal zone B cells, produce large quantities of anti-nuclear antibodies, and develop glomerulonephritis as early as 5 months of age (13;16-18). B cells from Lyn-/- mice are both hyperresponsive to BCR ligation and resistant to the inhibitory signals from FcγRIIb and CD22 (10-13). Peritoneal IgM+ B220+ B cell numbers were significantly lower in Lyn-/- mice at 2 months of age compared to wild-type mice and the size of the Peyer’s patches were reduced (17;18). As a result, CD5− B220high conventional B cells and B1 cells were also reduced (18). The Cress mice also exhibited a significant reduction in the frequency of peripheral B cell numbers. In addition, the function of the Cress B cells in mounting an antigen-specific immune response is deficient indicating that LynCress exhibits loss of function.
1) 94°C 2:00
The following sequence of 517 nucleotides is amplified (chromosome 4, + strand):
1 tgccactgag cagggcttct aaactctaca aggttgcttt tgtttgtttt ggcctcaggg
Primer binding sites are underlined and the sequencing primers are highlighted; the mutated nucleotide is shown in red.
1. Kurosaki, T., and Hikida, M. (2009) Tyrosine Kinases and their Substrates in B Lymphocytes. Immunol Rev. 228, 132-148.
2. Schwartzberg, P. L. (1998) The Many Faces of Src: Multiple Functions of a Prototypical Tyrosine Kinase. Oncogene. 17, 1463-1468.
3. Boggon, T. J., and Eck, M. J. (2004) Structure and Regulation of Src Family Kinases. Oncogene. 23, 7918-7927.
4. Rudd, C. E., Trevillyan, J. M., Dasgupta, J. D., Wong, L. L., and Schlossman, S. F. (1988) The CD4 Receptor is Complexed in Detergent Lysates to a Protein-Tyrosine Kinase (pp58) from Human T Lymphocytes. Proc Natl Acad Sci U S A. 85, 5190-5194.
5. Veillette, A., Bookman, M. A., Horak, E. M., and Bolen, J. B. (1988) The CD4 and CD8 T Cell Surface Antigens are Associated with the Internal Membrane Tyrosine-Protein Kinase p56lck. Cell. 55, 301-308.
6. Avila, M., Martinez-Juarez, A., Ibarra-Sanchez, A., and Gonzalez-Espinosa, C. (2012) Lyn Kinase Controls TLR4-Dependent IKK and MAPK Activation Modulating the Activity of TRAF-6/TAK-1 Protein Complex in Mast Cells. Innate Immun. 18, 648-660.
7. Verhagen, A. M., Wallace, M. E., Goradia, A., Jones, S. A., Croom, H. A., Metcalf, D., Collinge, J. E., Maxwell, M. J., Hibbs, M. L., Alexander, W. S., Hilton, D. J., Kile, B. T., and Starr, R. (2009) A Kinase-Dead Allele of Lyn Attenuates Autoimmune Disease Normally Associated with Lyn Deficiency. J Immunol. 182, 2020-2029.
8. Yamamoto, T., Yamanashi, Y., and Toyoshima, K. (1993) Association of Src-Family Kinase Lyn with B-Cell Antigen Receptor. Immunol Rev. 132, 187-206.
9. Guo, B., Su, T. T., and Rawlings, D. J. (2004) Protein Kinase C Family Functions in B-Cell Activation. Curr Opin Immunol. 16, 367-373.
10. Nishizumi, H., Horikawa, K., Mlinaric-Rascan, I., and Yamamoto, T. (1998) A Double-Edged Kinase Lyn: A Positive and Negative Regulator for Antigen Receptor-Mediated Signals. J Exp Med. 187, 1343-1348.
11. Chan, V. W., Lowell, C. A., and DeFranco, A. L. (1998) Defective Negative Regulation of Antigen Receptor Signaling in Lyn-Deficient B Lymphocytes. Curr Biol. 8, 545-553.
12. Smith, K. G., Tarlinton, D. M., Doody, G. M., Hibbs, M. L., and Fearon, D. T. (1998) Inhibition of the B Cell by CD22: A Requirement for Lyn. J Exp Med. 187, 807-811.
13. Chan, V. W., Meng, F., Soriano, P., DeFranco, A. L., and Lowell, C. A. (1997) Characterization of the B Lymphocyte Populations in Lyn-Deficient Mice and the Role of Lyn in Signal Initiation and Down-Regulation. Immunity. 7, 69-81.
14. Maeda, A., Kurosaki, M., Ono, M., Takai, T., and Kurosaki, T. (1998) Requirement of SH2-Containing Protein Tyrosine Phosphatases SHP-1 and SHP-2 for Paired Immunoglobulin-Like Receptor B (PIR-B)-Mediated Inhibitory Signal. J Exp Med. 187, 1355-1360.
15. Ho, L. H., Uehara, T., Chen, C. C., Kubagawa, H., and Cooper, M. D. (1999) Constitutive Tyrosine Phosphorylation of the Inhibitory Paired Ig-Like Receptor PIR-B. Proc Natl Acad Sci U S A. 96, 15086-15090.
16. Hibbs, M. L., Tarlinton, D. M., Armes, J., Grail, D., Hodgson, G., Maglitto, R., Stacker, S. A., and Dunn, A. R. (1995) Multiple Defects in the Immune System of Lyn-Deficient Mice, Culminating in Autoimmune Disease. Cell. 83, 301-311.
17. Nishizumi, H., Taniuchi, I., Yamanashi, Y., Kitamura, D., Ilic, D., Mori, S., Watanabe, T., and Yamamoto, T. (1995) Impaired Proliferation of Peripheral B Cells and Indication of Autoimmune Disease in Lyn-Deficient Mice. Immunity. 3, 549-560.
|Science Writers||Anne Murray|
|Authors||Kuan-Wen Wang, Jin Huk Choi, Ming Zeng, Apiruck Watthanasurorot, Bruce Beutler|