Tyrosine-protein kinase Lyn

UniProt P07948 Organism Homo sapiens Gene JTK8, LYN EC 2.7.10.2

Also known as: JTK8, LYN

Function

Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Involved in the regulation of endothelial activation, neutrophil adhesion and transendothelial migration. Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Mediates phosphorylation of the BCR-ABL fusion protein. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'. Kinase activity facilitates TLR4-TLR6 heterodimerization and signal initiation. Phosphorylates SCIMP on 'Tyr-107'; this enhances binding of SCIMP to TLR4, promoting the phosphorylation of TLR4, and a selective cytokine response to lipopolysaccharide in macrophages (By similarity). Phosphorylates CLNK (By similarity). Phosphorylates BCAR1/CAS and NEDD9/HEF1.

Classification

Family (Pfam): PF07714 PK_Tyr_Ser-Thr, PF00017 SH2, PF00018 SH3_1
InterPro: Kinase-like_dom_sf, Lyn_SH2, Lyn_SH3, Non-receptor_tyrosine_kinases, Prot_kinase_dom, Protein_kinase_ATP_BS, Ser-Thr/Tyr_kinase_cat_dom, SH2, SH2_dom_sf, SH3-like_dom_sf, SH3_domain, Tyr_kinase_AS, Tyr_kinase_cat_dom
Functional cluster: Protein Serine/Threonine Kinases

Experimental structures · PDB · 6

1W1F NMR
1WA7 NMR
3A4O X-ray 3.00A
5XY1 X-ray 2.70A
6NMW X-ray 1.20A
8WFF X-ray 1.30A

A predicted model is available from AlphaFold.

Gene Ontology · 118

Disease associations

autoinflammatory disease, systemic, with vasculitis MONDO:0957271

Drugs targeting this protein · 9

DASATINIB ANHYDROUS inhibitor
ILORASERTIB inhibitor
BAFETINIB inhibitor
BOSUTINIB inhibitor
JNJ-26483327 inhibitor
XL-228 inhibitor
TG100-801 inhibitor
ENMD-981693 inhibitor
TOLIMIDONE positive allosteric modulator

Neighborhood · nearest proteins

Nearest neighbours of Tyrosine-protein kinase Lyn: 3 by sequence/function similarity (left); 3 co-cited in the literature (right).

Related proteins · sequence + function similarity

Tyrosine-protein kinase Lyn 1.00
Tyrosine-protein kinase Lyn 1.00
Tyrosine-protein kinase HCK 0.97
Tyrosine-protein kinase HCK 0.96
Tyrosine-protein kinase Yes 0.96
Tyrosine-protein kinase Yes 0.95
Tyrosine-protein kinase Yes 0.95
Tyrosine-protein kinase Yes 0.95
Tyrosine-protein kinase Yes 0.95
Tyrosine-protein kinase Yes 0.95
Tyrosine-protein kinase HCK 0.95
Tyrosine-protein kinase transforming protein Yes 0.95

Co-cited proteins · studied together in the literature

Tyrosine-protein kinase Lyn 9 shared papers
Tyrosine-protein kinase CSK 1 shared papers
Tyrosine-protein kinase Lyn 1 shared papers
TOM1-like protein 1 1 shared papers
Megakaryocyte-associated tyrosine-protein kinase 2 shared papers
Phosphoprotein associated with glycosphingolipid-enriched microdomains 1 1 shared papers
Mast/stem cell growth factor receptor Kit 3 shared papers
Hematopoietic lineage cell-specific protein 1 shared papers
Latent membrane protein 2 1 shared papers
Low affinity immunoglobulin gamma Fc region receptor II-b 1 shared papers
B-cell antigen receptor complex-associated protein alpha chain 1 shared papers
B-lymphocyte antigen CD19 1 shared papers

Literature · 68 cited papers

Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome. Nat. Commun. · 2023
De Novo Gain-Of-Function Variations in LYN Associated With an Early-Onset Systemic Autoinflammatory Disorder. Arthritis Rheumatol. · 2023
N-terminome analysis of the human mitochondrial proteome. Proteomics · 2015
Global profiling of co- and post-translationally N-myristoylated proteomes in human cells. Nat. Commun. · 2014
An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
SCIMP, a transmembrane adapter protein involved in major histocompatibility complex class II signaling. Mol. Cell. Biol. · 2011
System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation. Sci. Signal. · 2011
Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2. Proc. Natl. Acad. Sci. U.S.A. · 2010
Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci. Signal. · 2010
CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat. Immunol. · 2010
Structural basis for the inhibitor recognition of human Lyn kinase domain. Bioorg. Med. Chem. Lett. · 2009
… and 56 more in the literature graph

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