Target General Infomation
Target ID
T68163
Former ID
TTDI02273
Target Name
Lyn tyrosine kinase
Gene Name
LYN
Synonyms
Lck/Yes-related novel protein tyrosine kinase; Tyrosine-protein kinase Lyn; V-yes-1 Yamaguchi sarcoma viral related oncogene homolog; p53Lyn; p56Lyn; LYN
Target Type
Clinical Trial
Disease Bone disease; Chronic lymphocytic leukaemia; Metastatic hormone refractory prostate cancer [ICD9:185; ICD10: M00-M99, C91, C61]
Cancer [ICD9: 140-229; ICD10: C00-C96]
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. 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, PTK2B/PYK2, 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.
BioChemical Class
Kinase
UniProt ID
EC Number
EC 2.7.10.2
Sequence
MGCIKSKGKDSLSDDGVDLKTQPVRNTERTIYVRDPTSNKQQRPVPESQLLPGQRFQTKD
PEEQGDIVVALYPYDGIHPDDLSFKKGEKMKVLEEHGEWWKAKSLLTKKEGFIPSNYVAK
LNTLETEEWFFKDITRKDAERQLLAPGNSAGAFLIRESETLKGSFSLSVRDFDPVHGDVI
KHYKIRSLDNGGYYISPRITFPCISDMIKHYQKQADGLCRRLEKACISPKPQKPWDKDAW
EIPRESIKLVKRLGAGQFGEVWMGYYNNSTKVAVKTLKPGTMSVQAFLEEANLMKTLQHD
KLVRLYAVVTREEPIYIITEYMAKGSLLDFLKSDEGGKVLLPKLIDFSAQIAEGMAYIER
KNYIHRDLRAANVLVSESLMCKIADFGLARVIEDNEYTAREGAKFPIKWTAPEAINFGCF
TIKSDVWSFGILLYEIVTYGKIPYPGRTNADVMTALSQGYRMPRVENCPDELYDIMKMCW
KEKAEERPTFDYLQSVLDDFYTATEGQYQQQP
Drugs and Mode of Action
Drug(s) Bafetinib Drug Info Phase 2 Bone disease; Chronic lymphocytic leukaemia; Metastatic hormone refractory prostate cancer [523198], [542828]
JNJ-26483327 Drug Info Phase 1 Cancer [522319]
Modulator Bafetinib Drug Info [1572591]
Inhibitor compound 23 Drug Info [528928]
JNJ-26483327 Drug Info [550422]
NG-25 Drug Info [532902]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Chemokine signaling pathway
NF-kappa B signaling pathway
Platelet activation
B cell receptor signaling pathway
Fc epsilon RI signaling pathway
Fc gamma R-mediated phagocytosis
Long-term depression
Epithelial cell signaling in Helicobacter pylori infection
Epstein-Barr virus infection
Viral carcinogenesis
NetPath Pathway IL2 Signaling Pathway
PANTHER Pathway B cell activation
Parkinson disease
CCKR signaling map ST
Pathway Interaction Database Fc-epsilon receptor I signaling in mast cells
BCR signaling pathway
LPA receptor mediated events
GMCSF-mediated signaling events
Glypican 1 network
Signaling events mediated by PTP1B
Regulation of p38-alpha and p38-beta
Thromboxane A2 receptor signaling
CXCR4-mediated signaling events
IL5-mediated signaling events
Class I PI3K signaling events
amb2 Integrin signaling
EPHA forward signaling
PDGFR-beta signaling pathway
IL8- and CXCR2-mediated signaling events
Signaling events mediated by Stem cell factor receptor (c-Kit)
EPO signaling pathway
IL8- and CXCR1-mediated signaling events
Ephrin B reverse signaling
Alpha-synuclein signaling
PathWhiz Pathway Fc Epsilon Receptor I Signaling in Mast Cells
Reactome GPVI-mediated activation cascade
Regulation of KIT signaling
Cell surface interactions at the vascular wall
FCGR activation
PECAM1 interactions
Fc epsilon receptor (FCERI) signaling
EPH-Ephrin signaling
Role of LAT2/NTAL/LAB on calcium mobilization
FCERI mediated MAPK activation
FCERI mediated Ca+2 mobilization
FCERI mediated NF-kB activation
CD28 co-stimulation
CTLA4 inhibitory signaling
EPHB-mediated forward signaling
EPHA-mediated growth cone collapse
EPH-ephrin mediated repulsion of cells
Dectin-2 family
CD209 (DC-SIGN) signaling
Platelet Adhesion to exposed collagen
Regulation of signaling by CBL
Growth hormone receptor signaling
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
WikiPathways Kit receptor signaling pathway
IL-3 Signaling Pathway
Fc epsilon receptor (FCERI) signaling
Signaling by the B Cell Receptor (BCR)
Signaling by SCF-KIT
Growth hormone receptor signaling
B Cell Receptor Signaling Pathway
TSLP Signaling Pathway
RANKL/RANK Signaling Pathway
Platelet Adhesion to exposed collagen
GPVI-mediated activation cascade
Costimulation by the CD28 family
Cell surface interactions at the vascular wall
IL-5 Signaling Pathway
References
Ref 522319ClinicalTrials.gov (NCT00676299) A Safety and Dose-finding Study of JNJ-26483327, a Drug in Development for Cancer, for Patients With Advanced and/or Refractory Solid Malignancies.. U.S. National Institutes of Health.
Ref 523198ClinicalTrials.gov (NCT01215799) Study of Bafetinib (INNO-406) as Treatment for Patients With Hormone-Refractory Prostate Cancer. U.S. National Institutes of Health.
Ref 542828(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7906).
Ref
Ref 528928Bioorg Med Chem Lett. 2007 Aug 1;17(15):4363-8. Epub 2007 Apr 13.N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of Lck: indazoles as phenol isosteres with improved pharmacokinetics.
Ref 532902Discovery of type II inhibitors of TGFbeta-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2). J Med Chem. 2015 Jan 8;58(1):183-96.
Ref 550422National Cancer Institute Drug Dictionary (drug id 596693).
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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