LYN
Encyclopedia
Tyrosine-protein kinase Lyn is a protein
that in humans is encoded in humans by the LYN gene
.
Lyn is a member of the Src family of protein tyrosine kinase
s, which is mainly expressed in hematopoietic cells
, in neural tissues liver, and adipose tissue. In various hematopoietic cells, Lyn has emerged as a key enzyme
involved in the regulation of cell activation. In these cells, a small amount of LYN is associated with cell surface receptor proteins, including the B cell antigen receptor (BCR), CD40, or CD19
.
and activation. LYN activation triggers a cascade of signaling event
s mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motif
s (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk
, phosholipase Cγ2
(PLCγ2) and phosphatidyl inositol-3 kinase
. These kinases provide activation signals, which play critical roles in proliferation, Ca2+ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motif
s (ITIM) in regulatory proteins such as CD22
, PIR-B and FCγRIIb1
. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatase
s such as SHIP-1
and SHP-1
, which further downmodulate signaling pathways, attenuate cell activation and can mediate tolerance. In B cell
s, Lyn sets the threshold of cell signaling and maintains the balance between activation and inhibition. Lyn thus functions as a rheostat that modulates signaling rather than as a binary on-off switch.
Lyn has also been implicated to have a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1). This phosphorylation of IRS1 leads to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization. In turn, activation of the insulin receptor has been shown to increase autophosphorylation of Lyn suggesting a possible feedback loop.
The insulin secretagogue, glimepiride (Amaryl®)
activates Lyn in adipocytes via the disruption of lipid rafts . This indirect Lyn activation may modulate the extrapancreatic glycemic control activity of glimepiride
Mice that expressed a hyperactive Lyn allele were tumor free and displayed no propensity toward hematological malignancy. These mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. With age these animals developed a glomerulonephritis phenotype associated with a 30% reduction in life expectancy.
Most recently LYN kinase inhibition with a novel small molecular inhibitor, bafetinib, appears to induce apoptosis in glioblastoma cells in preclinical models.
with IRS1
, PPP1R15A
, PLCG2
, Lymphocyte cytosolic protein 2
, MUC1
, CD117
, DOK1
, BCAR1
, TRPV4
, CD22
, INPP5D
, NEDD9
, GPVI
, Syk
, PTPRC, Cdk1
, Erythropoietin receptor
and Protein unc-119 homolog
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded in humans by the LYN gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Lyn is a member of the Src family of protein tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
s, which is mainly expressed in hematopoietic cells
Haematopoiesis
Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells...
, in neural tissues liver, and adipose tissue. In various hematopoietic cells, Lyn has emerged as a key enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
involved in the regulation of cell activation. In these cells, a small amount of LYN is associated with cell surface receptor proteins, including the B cell antigen receptor (BCR), CD40, or CD19
CD19
B-lymphocyte antigen CD19 also known as CD19 , is a protein that in humans is encoded by the CD19 gene.- Function :...
.
Function
Lyn has been described to have an inhibitory role in myeloid lineage proliferation. Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
and activation. LYN activation triggers a cascade of signaling event
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
s mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motif
Immunoreceptor tyrosine-based activation motif
An immunoreceptor tyrosine-based activation motif is a conserved sequence of four amino acids that is repeated twice in the cytoplasmic tails of certain cell surface proteins of the immune system....
s (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk
Syk
Spleen tyrosine kinase, also known as Syk, is an enyzme which in humans is encoded by the SYK gene.- Function :SYK, along with Zap-70, is a member of the Syk family of tyrosine kinases...
, phosholipase Cγ2
PLCG2
1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 is an enzyme that in humans is encoded by the PLCG2 gene.- Function :Enzymes of the phospholipase C family catalyze the hydrolysis of phospholipids to yield diacylglycerols and water-soluble phosphorylated derivatives of the lipid...
(PLCγ2) and phosphatidyl inositol-3 kinase
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
. These kinases provide activation signals, which play critical roles in proliferation, Ca2+ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motif
Immunoreceptor tyrosine-based inhibitory motif
An immunoreceptor tyrosine-based inhibition motif , is a conserved sequence of amino acids that is found in the cytoplasmic tails of many inhibitory receptors of the immune system...
s (ITIM) in regulatory proteins such as CD22
CD22
CD22 or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells...
, PIR-B and FCγRIIb1
FCGR2B
Low affinity immunoglobulin gamma Fc region receptor II-b is a protein that in humans is encoded by the FCGR2B gene. Mutation in the gene in humans leads to a lupus phenotype. The cytoplasmic part of this receptor contains an immunoreceptor tyrosine-based inhibitory motif.-Further reading:...
. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
s such as SHIP-1
INPP5D
Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 is an enzyme that in humans is encoded by the INPP5D gene.-Interactions:INPP5D has been shown to interact with DOK2, LYN, CD22, Grb2, CRKL, CD31, DOK1 and SHC1.-Further reading:...
and SHP-1
PTPN6
Tyrosine-protein phosphatase non-receptor type 6 is an enzyme that in humans is encoded by the PTPN6 gene.Also known as Src homology region 2 domain-containing phosphatase-1 .-Interactions:...
, which further downmodulate signaling pathways, attenuate cell activation and can mediate tolerance. In B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
s, Lyn sets the threshold of cell signaling and maintains the balance between activation and inhibition. Lyn thus functions as a rheostat that modulates signaling rather than as a binary on-off switch.
Lyn has also been implicated to have a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1). This phosphorylation of IRS1 leads to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization. In turn, activation of the insulin receptor has been shown to increase autophosphorylation of Lyn suggesting a possible feedback loop.
The insulin secretagogue, glimepiride (Amaryl®)
Glimepiride
Glimepiride is a medium-to-long acting sulfonylurea anti-diabetic drug. It is marketed as Amaryl by Sanofi-Aventis and GLIMY by Dr.Reddy's Labs...
activates Lyn in adipocytes via the disruption of lipid rafts . This indirect Lyn activation may modulate the extrapancreatic glycemic control activity of glimepiride
Pathology
Much of the current knowledge about Lyn has emerged from studies of genetically manipulated mice. Lyn deficient mice display a phenotype that includes splenomegaly, a dramatic increase in numbers of myeloid progenitors and moncyte/macrophage tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells.Mice that expressed a hyperactive Lyn allele were tumor free and displayed no propensity toward hematological malignancy. These mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. With age these animals developed a glomerulonephritis phenotype associated with a 30% reduction in life expectancy.
Most recently LYN kinase inhibition with a novel small molecular inhibitor, bafetinib, appears to induce apoptosis in glioblastoma cells in preclinical models.
Interactions
LYN has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with IRS1
IRS1
Insulin receptor substrate 1 is a protein that in humans is encoded by the IRS-1 gene.-Function:Insulin receptor substrate 1 plays a key role in transmitting signals from the insulin and insulin-like growth factor-1 receptors to intracellular pathways PI3K / Akt and Erk MAP kinase...
, PPP1R15A
PPP1R15A
Protein phosphatase 1 regulatory subunit 15A is an enzyme that in humans is encoded by the PPP1R15A gene.-Interactions:PPP1R15A has been shown to interact with PPP1CB, PPP1CA, PPP1CC, SMARCB1, LYN, TSN, BAG1 and MLL.-Further reading:...
, PLCG2
PLCG2
1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase gamma-2 is an enzyme that in humans is encoded by the PLCG2 gene.- Function :Enzymes of the phospholipase C family catalyze the hydrolysis of phospholipids to yield diacylglycerols and water-soluble phosphorylated derivatives of the lipid...
, Lymphocyte cytosolic protein 2
Lymphocyte cytosolic protein 2
Lymphocyte cytosolic protein 2 , also known as LCP2 or SLP-76, is a gene that encodes a signal-transducing adaptor protein.-Interactions:...
, MUC1
MUC1
Mucin 1, cell surface associated or polymorphic epithelial mucin is a mucin encoded by the MUC1 gene in humans. MUC1 is a proteoglycan with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and...
, CD117
CD117
Mast/stem cell growth factor receptor also known as proto-oncogene c-Kit or tyrosine-protein kinase Kit or CD117 is a protein that in humans is encoded by the KIT gene...
, DOK1
DOK1
Docking protein 1 is a protein that in humans is encoded by the DOK1 gene.-Interactions:DOK1 has been shown to interact with RET proto-oncogene, SH2D1A, LYN, RAS p21 protein activator 1, INPP5D, CD117, SHC1, Abl gene and TEC.-Further reading:...
, BCAR1
BCAR1
Breast cancer anti-estrogen resistance protein 1 is a protein that in humans is encoded by the BCAR1 gene.-External links:* Info with links in the...
, TRPV4
TRPV4
Transient receptor potential cation channel subfamily V member 4 is a protein that in humans is encoded by the TRPV4 gene.This gene encodes TRPV4, a member of the OSM9-like transient receptor potential channel subfamily in the transient receptor potential superfamily of ion channels...
, CD22
CD22
CD22 or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells...
, INPP5D
INPP5D
Phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 is an enzyme that in humans is encoded by the INPP5D gene.-Interactions:INPP5D has been shown to interact with DOK2, LYN, CD22, Grb2, CRKL, CD31, DOK1 and SHC1.-Further reading:...
, NEDD9
NEDD9
Enhancer of filamentation 1 is a protein that in humans is encoded by the NEDD9 gene.-Interactions:NEDD9 has been shown to interact with ID2, LYN, NCK1, MICAL1, CDH1, Abl gene, PTK2, CRKL, CRK and Mothers against decapentaplegic homolog 3....
, GPVI
GPVI
Glycoprotein VI also known as GPVI is a glycoprotein receptor for collagen which is expressed in platelets. In humans, glycoprotein VI is encoded by the GPVI gene.- Function :...
, Syk
Syk
Spleen tyrosine kinase, also known as Syk, is an enyzme which in humans is encoded by the SYK gene.- Function :SYK, along with Zap-70, is a member of the Syk family of tyrosine kinases...
, PTPRC, Cdk1
Cdk1
Cyclin dependent kinase 1 also known as Cdk1 or cell division control protein 2 homolog is a highly conserved protein that functions as a serine/threonine kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S....
, Erythropoietin receptor
Erythropoietin receptor
The erythropoietin receptor is a protein that in humans is encoded by the EPOR gene. EpoR is a 59 kDa peptide and is a member of the cytokine receptor family. EpoR pre-exists as dimers...
and Protein unc-119 homolog
Protein unc-119 homolog
Protein unc-119 homolog A is a protein that in humans is encoded by the UNC119 gene.-Interactions:Protein unc-119 homolog has been shown to interact with Lck, ARL3, ARL2, LYN, Interleukin 5 receptor alpha subunit, CD247, CD4 and FYN....
.