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FLASH GENE

Symbol

LCK

contributors: mct/pgu - updated : 16-02-2016

HGNC name	lymphocyte-specific protein tyrosine kinase
HGNC id	6524

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	IMD22 Immunodeficiency 22
Location	1p35.2      Physical location : 32.716.839 - 32.751.765
Synonym name	proto-oncogene tyrosine-protein kinase LCK
	p56(LSTRA) protein-tyrosine kinase
	T cell-specific protein-tyrosine kinase
Synonym symbol(s)	RP4-675E8.4, LSK, YT16, p56lck, pp58lck
EC.number	2.7.1.112, 2.7.10.1

DNA

TYPE	functioning gene
STRUCTURE	34.93 kb     13 Exon(s)

Genomic sequence alignment details
10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

Physical map

RNA

TRANSCRIPTS	type

text	long and short isoforms

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001042771 13 - 2118 NP_001036236 - 509 - 2011 21339332 NM_005356 13 - 2135 NP_005347 - 509 - 2011 21339332

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Lymphoid/Immune lymph node       highly   spleen       highly   thymus       highly Homo sapiens Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid

cells

System Cell Pubmed Species Stage Rna symbol Blood/Hematopoietic progenitor cell Lymphoid/Immune lymphocyte Lymphoid/Immune T cell Homo sapiens

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a SH3, controling T lymphocyte activation by regulating MAPK pathway induction
	a SH2 domains mediating interaction with SQSTM1, interaction regulated by ser-58 phosphorylation
	a kinase domain alone is sufficient to bind SOCS1

HOMOLOGY

Homologene

FAMILY	protein kinase superfamily
	Tyr protein kinase family
	SRC subfamily

CATEGORY

protooncogene

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus
text	may be recruited to the plasma membrane by RHOH, which also binds CSK, resulting in LCK inactivation
	oncogenic LCK kinase translocates to the nucleus and binds to the LMO2 gene promoter

basic FUNCTION	playing an essential role for the selection and maturation of developing T-cell in the thymus and in mature T-cell function
	plays a key role in targeting HIV-1 Gag to the plasma membrane in T cells
	protects cells from glucocorticoid-induced apoptosis and its inhibition enhances sensitivity to dexamethasone
	role for LCK in the regulation of Th2-type immunity
	plays essential roles in development, antigen-induced T cell activation, and proliferation
	essential for activation of mature T cells
	non-receptor tyrosine kinase, critically involved in fractionated radiation-induced expansion of the glioma-initiating cell population and decreased cellular sensitivity to anticancer treatments
	LCK signaling is required, at the immunological synapse, for the centrosome to dock at the plasma membrane
	plays a key role in T cell signal transduction and is tightly regulated by phosphorylation and dephosphorylation
	oncogenic LCK can initiate multiple signaling cascades that are likely to be controlled by the spatial localization of the oncoprotein
	regulation of the cellular location and activation of LCK in maturing thymocytes is a key regulatory mechanism to prevent T-cell responses to self-antigens
	major role for LCK in proximal and distal B-cell receptor-mediated signaling in chronic lymphocytic leukemia cells
	mediates ITGB1 signalling to regulate Schwann cell migration and myelination
	plays a crucial role in the T-cell response by transducing early activation signals triggered by TCR (T-cell receptor) engagement
	T cell receptor (TCR) phosphorylation requires the kinase LCK and phosphatase PTPRC
	LCK, which plays a unique role in enforcing MHC restriction, is essential for thymic development in presence or absence of CBL, ensuring MHC restriction of T cells derived from either pathway
	is an Src family kinases (SFKs) that is central to the initiation of T cell activation in response to ligand binding to the T cell receptor (TCR) and is also critical for later signaling processes
	kinase activity of LCK requires both the phosphorylation of an activating tyrosine residue and the dephosphorylation of an inhibitory tyrosine residue
	kinase activity of ZAP70 stimulates negative feedback pathways that target LCK and thereby modulate the phosphorylation patterns of the immunoreceptor tyrosine-based activation motifs (ITAMs) of the CD3 and zeta chain components of the TCR
	novel function of nuclear LCK in promoting human leukemic T cell survival through interaction with a tumor suppressor
	is a key T-cell kinase and widely implicated in blood malignancies
	role of mitochondrial LCK in metabolic reprogramming of leukemic cells

CELLULAR PROCESS	cell life, proliferation/growth

PHYSIOLOGICAL PROCESS

development

text	T cell development and function

PATHWAY

metabolism

signaling

signal transduction

RAS signaling pathway

a component

ITGB2/LCK/ZAP70 complex is in position to initiate the rapid adhesion strengthening and migration necessary for T-lymphocyte responses when stimulated vasculature is encountered at sites of infection or injury

INTERACTION

DNA

RNA

small molecule	nucleotide,
	ATP

protein	mediating phosphorylation of DOK proteins
	interaction between PRKD2 and LCK (LCK regulated the activity of PRKD2 by tyrosine phosphorylation, which in turn may have modulated the physiological functions of PKD2 during TCR-induced T cell activation)
	anchoring CD4 to lipid microdomains (rafts) on microvilli
	interacts with RASSF5 through its C-terminal Src homology 2 binding motif and LCK-mediated phosphorylation is critical for the efficient translocation of RASSF5 into the nuclear compartment
	SH2D2A through its interaction with both ITK and LCK, primes ITK for LCK mediated phosphorylation and thereby regulates CXCL12 induced T cell migration and actin cytoskeleton rearrangements
	RHOH binds and modulates LCK, the non-receptor tyrosine kinase crucial in initiating pre-TCR and TCR signallings
	LAT promotes TCR signal initiation, suggesting that this adaptor may contribute to maintain active LCK in proximity of their substrates
	ITGB2 is constitutively associated with the protein tyrosine kinases LCK and ZAP70
	oncogenic LCK may activate LMO2 promoter through direct interaction
	oncogenic LCK and JAK2 may utilize different mechanisms to upregulate LMO2 levels during oncogenic transformation
	DLG1, which acts as a scaffold for many signaling molecules including the TCR and LCK, could mediate the cellular redistribution of LCK during T-cell maturation
	upregulates FOXP3 by tyrosine phosphorylation, resulting in decreased MMP9, SKP2, and VEGFA expression, and suppressed cellular invasion
	PTK2 negatively regulates LCK function downstream of the T cell antigen receptor
	spatial regulation of LCK by PTPRC and GM1 ganglioside determines the outcome of apoptotic response to LGALS1 and this local regulation may occur only upon intimate effector (LGALS1 expressing) cell-T-cell attachment
	prominent immunoregulatory function of LGALS1, is induction of apoptosis in activated T-cells by a process depending on the activity of SRC family tyrosine kinase, LCK
	both SLAMF6-associated LCK phosphorylation and kinase activity were enhanced in restimulated T cells, amplifying proximal TCR signaling
	SH2D1A facilitates recruitment and activation of LCK at SLAMF6 receptors during restimulation-induced cell death
	IGF2R specifically controls the balance between active and inactive LCK in resting T cells, which guarantees operative T cell effector functions
	in T-cells, cholesterol-dependent membrane domains function in the regulation of the Src family kinase LCK by sequestering LCK from its activator PTPRC
	in a kinase-independent manner, mitochondrial LCK interferes with mitochondrial translational machinery through competitive binding to GADD45GIP1

cell & other

membrane associated

REGULATION

inhibited by	negatively regulated by CB1 ubiquitin ligase
	SOCS6 (negative regulator of LCK)

repressed by

dexamethasone that downregulates LCK, which, in turn, suppresses lymphocyte activation by inhibiting pro-survival calcium oscillations

Other

regulated by SOCS1 (important role of SOCS in regulating LCK functions)

ASSOCIATED DISORDERS

corresponding disease(s)

IMD22

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral   translocation     breakpoint in T-cell acute lymphoblastic leukemia with translocations t(1;7)(p34;q34 constitutional     --low   in one case of SCID(severe combined immunodeficiency) tumoral     --over   in lymphomas of germinal center origin (e.g. follicular lymphoma) and also many mantle cell lymphomas, chronic lymphocytic leukemia (CLL) and most T-cell neoplasms

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer hemopathy   small-molecule inhibitors of Lck, such as dasatinib, may function to reverse glucocorticoid resistance in some lymphoid malignancies

ANIMAL & CELL MODELS