Reviewed, UniProtKB/Swiss-Prot P06240 (LCK_MOUSE)

Names and origin

Protein names

Recommended name:
    Proto-oncogene tyrosine-protein kinase LCK
    EC=2.7.10.2
Alternative name(s):
    Lymphocyte cell-specific protein-tyrosine kinase
    p56-LCK
    LSK

Gene names

Name:	Lck
Synonyms:	Lsk-t

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	509 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Tyrosine kinase that plays an essential role for the selection and maturation of developing T-cell in the thymus and in mature T-cell function. Is constitutively associated with the cytoplasmic portions of the CD4 and CD8 surface receptors and plays a key role in T-cell antigen receptor(TCR)-linked signal transduction pathways. Association of the TCR with a peptide antigen-bound MHC complex facilitates the interaction of CD4 and CD8 with MHC class II and class I molecules, respectively, and thereby recruits the associated LCK to the vicinity of the TCR/CD3 complex. LCK then phosphorylates tyrosines residues within the immunoreceptor tyrosines-based activation motifs (ITAMs) in the cytoplasmic tails of the TCRgamma chains and CD3 subunits, initiating the TCR/CD3 signaling pathway. In addition, contributes to signaling by other receptor molecules. Associates directly with the cytoplasmic tail of CD2, and upon engagement of the CD2 molecule, LCK undergoes hyperphosphorylation and activation. Also plays a role in the IL2 receptor-linked signaling pathway that controls T-cell proliferative response. Binding of IL2 to its receptor results in increased activity of LCK. Is expressed at all stages of thymocyte development and is required for the regulation of maturation events that are governed by both pre-TCR and mature alpha beta TCR By similarity.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme regulation	Inhibited by tyrosine phosphorylation By similarity.
Subunit structure	Binds to the cytoplasmic domain of cell surface receptors, such as CD2, CD4, CD5, CD8, CD44, CD45 and CD122. Also binds to effector molecules, such as PI4K, VAV1, RASA1, FYB and to other protein kinases including CDC2, RAF1, ZAP70 and SYK. Binds to phosphatidylinositol 3'-kinase (PI3K) from T-lymphocytes through its SH3 domain and to the tyrosine phosphorylated form of KHDRBS1/p70 through its SH2 domain. Interacts with SQSTM1. Interacts with phosphorylated LIME1. Interacts with CBLB and PTPRH By similarity.
Subcellular location	Cytoplasm. Cell membrane; Lipid-anchor; Cytoplasmic side. Note= Present in lipid rafts in an unactive form.
Tissue specificity	Present at a low level in most T-cells, and at an elevated level in LSTRA and THY 19 (T-cell lymphoma) cells.
Developmental stage	Levels remain relatively constant throughout T-cell ontogeny.
Domain	The SH2 domain mediates interaction with SQSTM1. Interaction is regulated by Ser-59 phosphorylation By similarity.
Post-translational modification	Phosphorylated on Tyr-394, which increases enzymatic activity. Phosphorylated on Tyr-505, presumably by CSK, which decreases activity. Myristoylation is required prior to palmitoylation.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. Contains 1 protein kinase domain. Contains 1 SH2 domain. Contains 1 SH3 domain.

Ontologies

Keywords
Cellular component	Cell membrane Cytoplasm Membrane
Disease	Proto-oncogene
Domain	SH2 domain SH3 domain
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Lipoprotein Myristate Palmitate Phosphoprotein
Gene Ontology (GO)
Biological process	B cell receptor signaling pathway Inferred from direct assay. Source: MGI caspase activation Inferred from sequence or structural similarity. Source: UniProtKB cellular zinc ion homeostasis Inferred from sequence or structural similarity. Source: UniProtKB induction of apoptosis Inferred from sequence or structural similarity. Source: UniProtKB peptidyl-tyrosine phosphorylation Inferred from direct assay. Source: MGI positive regulation of gamma-delta T cell differentiation Inferred from mutant phenotype. Source: MGI protein amino acid autophosphorylation Inferred from direct assay. Source: MGI regulation of T cell receptor signaling pathway Inferred from direct assay. Source: MGI release of sequestered calcium ion into cytosol Inferred from direct assay. Source: UniProtKB response to drug Inferred from sequence or structural similarity. Source: UniProtKB
Cellular component	membrane raft Inferred from sequence or structural similarity. Source: UniProtKB pericentriolar material Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	SH2 domain binding Inferred from sequence or structural similarity. Source: UniProtKB protein serine/threonine phosphatase activity Inferred from sequence or structural similarity. Source: UniProtKB protein tyrosine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
	O92969	2	EBI-1401,EBI-710506	From a different organism.
	P26660	1	EBI-1401,EBI-706322	From a different organism.
	P27958	3	EBI-1401,EBI-706378	From a different organism.
Cd4	P06332	2	EBI-1401,EBI-1404
Hcls1	P49710	1	EBI-1401,EBI-924601
KHDRBS1	Q07666	1	EBI-1401,EBI-1364	From a different organism.
SH2D2A	Q9NP31	1	EBI-1401,EBI-490630	From a different organism.
Sh2d2a	Q9QXK9	1	EBI-1401,EBI-1644

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view
Molecule processing
	Initiator methionine	1	1	Removed Probable
	Chain	2 – 509	508	Proto-oncogene tyrosine-protein kinase LCK
Regions
	Domain	61 – 121	61	SH3
	Domain	127 – 224	98	SH2
	Domain	245 – 498	254	Protein kinase
	Nucleotide binding	251 – 259	9	ATP By similarity
	Region	2 – 72	71	Interactions with CD4 and CD8
	Region	154 – 242	89	Interaction with PTPRH By similarity
Sites
	Active site	364	1	Proton acceptor By similarity
	Binding site	273	1	ATP By similarity
Amino acid modifications
	Modified residue	162	1	Phosphoserine By similarity
	Modified residue	192	1	Phosphotyrosine By similarity
	Modified residue	213	1	Phosphoserine By similarity
	Modified residue	394	1	Phosphotyrosine; by autocatalysis
	Modified residue	501	1	Phosphothreonine By similarity
	Modified residue	505	1	Phosphotyrosine Probable
	Lipidation	2	1	N-myristoyl glycine Probable
	Lipidation	3	1	S-palmitoyl cysteine
	Lipidation	5	1	S-palmitoyl cysteine
Experimental info
	Mutagenesis	2	1	G → A: Abolishes myristoylation and palmitoylation
	Mutagenesis	3 – 5	3	CVC → SVK: Complete loss of interaction with CD4 or CD8
	Mutagenesis	3	1	C → S: Abolishes plasma membrane association; when associated with S-41. Reduced palmitoylation level
	Mutagenesis	5	1	C → K: Reduced palmitoylation level
	Mutagenesis	5	1	C → S: Abolishes plasma membrane association; when associated with S-21
	Mutagenesis	20	1	C → S: Complete loss of interaction with CD4 or CD8
	Mutagenesis	23	1	C → S: Complete loss of interaction with CD4 or CD8
	Mutagenesis	269	1	K → N: Reduced activity
	Mutagenesis	270	1	V → L: Reduced activity
	Mutagenesis	271	1	A → S: Reduced activity
	Mutagenesis	272	1	V → A: Reduced activity
	Mutagenesis	273	1	K → R: Loss of activity
	Mutagenesis	274	1	S → N: Reduced activity
	Mutagenesis	275	1	L → M: Reduced activity
	Mutagenesis	276	1	K → V: Reduced activity
	Mutagenesis	505	1	Y → F: Causes thymic tumors

Sequences

	Sequence		Length	Mass (Da)
	P06240-1 [UniParc]. Last modified January 23, 2007. Version 4. Checksum: 3513102F49A7FD0B	FASTA	509	57,943
	10 20 30 40 50 60 MGCVCSSNPE DDWMENIDVC ENCHYPIVPL DSKISLPIRN GSEVRDPLVT YEGSLPPASP 70 80 90 100 110 120 LQDNLVIALH SYEPSHDGDL GFEKGEQLRI LEQSGEWWKA QSLTTGQEGF IPFNFVAKAN 130 140 150 160 170 180 SLEPEPWFFK NLSRKDAERQ LLAPGNTHGS FLIRESESTA GSFSLSVRDF DQNQGEVVKH 190 200 210 220 230 240 YKIRNLDNGG FYISPRITFP GLHDLVRHYT NASDGLCTKL SRPCQTQKPQ KPWWEDEWEV 250 260 270 280 290 300 PRETLKLVER LGAGQFGEVW MGYYNGHTKV AVKSLKQGSM SPDAFLAEAN LMKQLQHPRL 310 320 330 340 350 360 VRLYAVVTQE PIYIITEYME NGSLVDFLKT PSGIKLNVNK LLDMAAQIAE GMAFIEEQNY 370 380 390 400 410 420 IHRDLRAANI LVSDTLSCKI ADFGLARLIE DNEYTAREGA KFPIKWTAPE AINYGTFTIK 430 440 450 460 470 480 SDVWSFGILL TEIVTHGRIP YPGMTNPEVI QNLERGYRMV RPDNCPEELY HLMMLCWKER 490 500 PEDRPTFDYL RSVLDDFFTA TEGQYQPQP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A lymphocyte-specific protein-tyrosine kinase gene is rearranged and overexpressed in the murine T cell lymphoma LSTRA." Marth J.D., Peet R., Krebs E.G., Perlmutter R.M. Cell 43:393-404(1985) [PubMed: 2416464] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Expression of a new tyrosine protein kinase is stimulated by retrovirus promoter insertion." Voronova A.F., Sefton B.M. Nature 319:682-685(1986) [PubMed: 3081813] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed: 16141072] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: NOD. Tissue: Thymus.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: FVB/N. Tissue: Salivary gland.
[5]	"Structure of the murine lck gene and its rearrangement in a murine lymphoma cell line." Garvin A.M., Pawar S., Marth J.D., Perlmutter R.M. Mol. Cell. Biol. 8:3058-3064(1988) [PubMed: 2850479] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-35.
[6]	"Two lck transcripts containing different 5' untranslated regions are present in T cells." Voronova A.F., Adler H.T., Sefton B.M. Mol. Cell. Biol. 7:4407-4413(1987) [PubMed: 3501824] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-11.
[7]	"Avian reovirus mRNAs are nonfunctional in infected mouse cells: translational basis for virus host-range restriction." Amrein K.E., Sefton B.M. Proc. Natl. Acad. Sci. U.S.A. 85:4257-4261(1988) [PubMed: 3380790] [Abstract] Cited for: MUTAGENESIS OF TYR-505.
[8]	"Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs." Turner J.M., Brodsky M.H., Irving B.A., Levin S.D., Perlmutter R.M., Littman D.R. Cell 60:755-765(1990) [PubMed: 2107025] [Abstract] Cited for: INTERACTION WITH CD4 AND CD8, MUTAGENESIS OF 3-CYS--CYS-5; CYS-20 AND CYS-23.
[9]	"Creation and characterization of temperature-sensitive mutants of the lck tyrosine protein kinase." Hurley T.R., Amrein K.E., Sefton B.M. J. Virol. 66:7406-7413(1992) [PubMed: 1279202] [Abstract] Cited for: MUTAGENESIS.
[10]	"Enhancement of T-cell responsiveness by the lymphocyte-specific tyrosine protein kinase p56lck." Abraham N., Miceli M.C., Parnes J.C., Veillette A. Nature 350:62-66(1991) [PubMed: 1706070] [Abstract] Cited for: MUTAGENESIS OF LYS-273.
[11]	"Thymic tumorigenesis induced by overexpression of p56lck." Abraham K.M., Levin S.D., Marth J.D., Forbush K.A., Perlmutter R.M. Proc. Natl. Acad. Sci. U.S.A. 88:3977-3981(1991) [PubMed: 1708890] [Abstract] Cited for: PHOSPHORYLATION AT TYR-505, MUTAGENESIS OF TYR-505.
[12]	"Negative regulation of T-cell receptor signalling by tyrosine protein kinase p50csk." Chow L.M., Fournel M., Davidson D., Veillette A. Nature 365:156-160(1993) [PubMed: 8371758] [Abstract] Cited for: PHOSPHORYLATION BY CSK.
[13]	"The conserved lysine of the catalytic domain of protein kinases is actively involved in the phosphotransfer reaction and not required for anchoring ATP." Carrera A.C., Alexandrov K., Roberts T.M. Proc. Natl. Acad. Sci. U.S.A. 90:442-446(1993) [PubMed: 8421674] [Abstract] Cited for: MUTAGENESIS.
[14]	"Palmitylation of an amino-terminal cysteine motif of protein tyrosine kinases p56lck and p59fyn mediates interaction with glycosyl-phosphatidylinositol-anchored proteins." Shenoy-Scaria A.M., Timson L.K., Kwong J., Shaw A.S., Lublin D.M. Mol. Cell. Biol. 13:6385-6392(1993) [PubMed: 8413237] [Abstract] Cited for: PALMITOYLATION AT CYS-3 AND CYS-5, MUTAGENESIS OF CYS-3 AND CYS-5.
[15]	"Palmitoylation of multiple Src-family kinases at a homologous N-terminal motif." Koegl M., Zlatkine P., Ley S.C., Courtneidge S.A., Magee A.I. Biochem. J. 303:749-753(1994) [PubMed: 7980442] [Abstract] Cited for: PALMITOYLATION AT CYS-3 AND CYS-5, MYRISTOYLATION AT GLY-2, MUTAGENESIS OF GLY-2; CYS-3 AND CYS-5.
[16]	"Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b." Bachmaier K., Krawczyk C., Kozieradzki I., Kong Y.-Y., Sasaki T., Oliveira-dos-Santos A., Mariathasan S., Bouchard D., Wakeham A., Itie A., Le J., Ohashi P.S., Sarosi I., Nishina H., Lipkowitz S., Penninger J.M. Nature 403:211-216(2000) [PubMed: 10646608] [Abstract] Cited for: INTERACTION WITH CBLB.
[17]	"Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells." Yasuda K., Nagafuku M., Shima T., Okada M., Yagi T., Yamada T., Minaki Y., Kato A., Tani-Ichi S., Hamaoka T., Kosugi A. J. Immunol. 169:2813-2817(2002) [PubMed: 12218089] [Abstract] Cited for: SUBCELLULAR LOCATION.
[18]	"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells." Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., Zha X.-M., Polakiewicz R.D., Comb M.J. Nat. Biotechnol. 23:94-101(2005) [PubMed: 15592455] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-394, MASS SPECTROMETRY.

Cross-references

Sequence databases
EMBLGenBankDDBJ	M12056 mRNA. Translation: AAB59674.1. X03533 mRNA. Translation: CAA27234.1. X03533 mRNA. Translation: CAA27235.1. Sequence problems. X03533 mRNA. Translation: CAA27236.1. Sequence problems. AK088001 mRNA. Translation: BAC40086.1. BC011474 mRNA. Translation: AAH11474.1. M21511 Genomic DNA. Translation: AAA39422.1. Sequence problems. M18098 Genomic DNA. Translation: AAA39421.1.
PIR	I48845.
RefSeq	NP_034823.1.
UniGene	Mm.293753
3D structure databases
HSSP	HSSP built from PDB template 1H92 based on UniProtKB P06239.
SMR	P06240. Positions 65-509.
ModBase	Search...
Protein-protein interaction databases
IntAct	P06240.
PTM databases
PhosphoSite	P06240.
Genome annotation databases
Ensembl	ENSMUSG00000000409. Mus musculus. [Contig view]
GeneID	16818.
KEGG	mmu:16818.
Organism-specific databases
MGI	MGI:96756. Lck.
Phylogenomic databases
HOGENOM	P06240.
HOVERGEN	P06240.
Gene expression databases
ArrayExpress	P06240.
CleanEx	MM_LCK.
GermOnline	ENSMUSG00000000409. Mus musculus.
Family and domain databases
InterPro	IPR000719. Prot_kinase_core. IPR017441. Protein_kinase_ATP_bd_CS. IPR000980. SH2. IPR001452. SH3. IPR001245. Tyr_pkinase. IPR008266. Tyr_pkinase_AS. [Graphical view]