|Coordinate||3,745,330 bp (GRCm38)|
|Base Change||G ⇒ T (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||Tryptophan changed to Cysteine|
|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: W99C
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
AA Change: W78C
|Predicted Effect||probably damaging
PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
|Meta Mutation Damage Score||0.9452|
|Is this an essential gene?||Non Essential (E-score: 0.000)|
|Candidate Explorer Status||CE: excellent candidate; Verification probability: 0.722; ML prob: 0.67; human score: 0|
Linkage Analysis Data
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Semidominant|
|Last Updated||2019-09-04 9:44 PM by Diantha La Vine|
|Record Created||2015-12-08 11:59 PM by Bruce Beutler|
The Pacific phenotype was identified among G3 mice of the pedigree R3736, some of which showed an increased frequency of B1 cells (Figure 1), an increased frequency of CD11c+ dendritic cells (Figure 2), an increased frequency of macrophages (Figure 3), a reduced frequency of natural killer cells (Figure 4), and a reduced frequency of T cells (Figure 5) including CD4+ T cells (Figure 6) and CD8+ T cells (Figure 7), all in the peripheral blood.
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 49 mutations. All of the above anomalies were linked by continuous variable mapping to a mutation in Lyn: a G to T transversion at base pair 3,745,330 (v38) on chromosome 4, or base pair 67,210 in the GenBank genomic region NC_000070 encoding Lyn. The strongest association was found with an additive model of linkage to the normalized macrophage frequency, wherein 23 variant homozygotes and 38 heterozygotes departed phenotypically from 23 homozygous reference mice with a P value of 2.49 x 10-13 (Figure 8). A substantial semidominant effect was observed in most of the assays but the mutation is preponderantly recessive, and in no assay was a purely dominant effect observed.
The mutation corresponds to residue 546 in the mRNA sequence NM_001111096 (variant 1) within exon 5 of 13 total exons as well as residue 483 in the mRNA sequence NM_10747 (variant 2) within exon 5 or 13 total exons.
Genomic numbering corresponds to NC_000070. The mutated nucleotide is indicated in red. The mutation results in a tryptophan (W) to cysteine (C) substitution at position 99 (W99C) in the LYN protein, and is strongly predicted by PolyPhen-2 to be damaging (score = 1.000) (1).
|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 6; 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 Pacific mutation (W99C) occurs in SH3 domain in both Lyn isoforms. The SH3 domain of Lyn mediates protein-protein interactions between Lyn and Pro-rich motif-containing proteins.
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 Pacific mice did not exhibit reduced frequencies of peripheral B cell numbers, indicating that some Lyn function may persist in the Pacific mice.
1) 94°C 2:00
The following sequence of 401 nucleotides is amplified (chromosome 4, + strand):
1 ttctcttcta tagggcactg caagccatat tgaagttgaa acgatgtttt tttatttttg
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|
|Illustrators||Peter Jurek, Katherine Timer|
|Authors||Ming Zeng, Xue Zhong, and Bruce Beutler|